CN114401732A

CN114401732A - CD38 binding agents and uses thereof

Info

Publication number: CN114401732A
Application number: CN202080061542.3A
Authority: CN
Inventors: L·拉斯泰利; M·E·韦尔施; A·布宁; A·M·K·罗西; T·蓓尔巴索娃
Original assignee: Cleo Pharmaceutical Co ltd
Current assignee: Cleo Pharmaceutical Co ltd
Priority date: 2019-07-03
Filing date: 2020-06-24
Publication date: 2022-04-26
Also published as: WO2021003050A3; EP3993818A2; WO2021003050A2; KR20220042130A; CA3143513A1; JP2022539258A; AU2020299157A1; US20230028880A1; EP3993818A4; IL289531A

Abstract

The present disclosure provides, inter alia, compounds comprising an antibody binding moiety and a CD38 binding targeting moiety. In some embodiments, provided compounds recruit different types of antibodies to diseased cells, such as cancer cells, and induce immune activity to kill such cells. The provided technology is applicable to the treatment of various diseases including cancer.

Description

CD38 binding agents and uses thereof

Cross Reference to Related Applications

This application claims priority from 62/870,633 No. 62/870,633 filed on 7/03/2019 and U.S. provisional application No. 62/951,765 filed on 12/20/2019, each of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure provides, inter alia, techniques (e.g., compounds, compositions, and methods thereof) useful, for example, in the treatment of various conditions, disorders, or diseases.

Background

Immune system activity can be utilized to prevent or treat a variety of conditions, disorders and diseases.

Disclosure of Invention

In some embodiments, the present disclosure provides techniques, e.g., compounds, compositions, methods, etc., that are particularly useful for recruiting antibodies to damaged or defective tissues (e.g., tumors, certain wounds, etc.), foreign objects or entities (e.g., infectious agents), etc., including CD38 or fragments thereof. In some embodiments, the provided techniques can trigger, generate, promote, and/or enhance immune system activity, e.g., antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), etc., against target cells, tissues, subjects, and/or entities expressing CD 38. In some embodiments, the present disclosure is directed to the design, preparation, and use of molecules capable of selectively redirecting endogenous antibodies to diseased cells expressing CD38 (e.g., cancer cells) and inducing immune system activity (e.g., antibody-directed cell-mediated immune responses, e.g., cytotoxicity, ADCP, etc.).

In some embodiments, the present disclosure provides an Antibody Recruiting Molecule (ARM) comprising an antibody binding portion, a target binding portion (e.g., a target binding portion that binds to CD 38), and an optional linker portion. In some embodiments, the target binding moiety confers specificity to ARM for its target (e.g., a diseased cell of interest) via, for example, binding to an entity that distinguishes the target from non-targets (e.g., diseased cells from other cell types). In addition, ARM can achieve target-specific recruitment of antibodies (e.g., endogenous antibodies, administered antibodies, etc.) via ABT, and/or trigger, generate, promote, and/or enhance immune activity, such as immune-mediated killing of target cells. In some embodiments, the provided technology includes an ARM comprising a target binding moiety that binds CD38, and can selectively recruit antibodies to a target expressing CD38 (e.g., a cancer cell) and/or trigger, generate, promote, and/or enhance immune activity (e.g., ADCC, ADCP, etc.) against such target cells. In some embodiments, the target cell expressing CD is a cancer cell. In some embodiments, the agents provided herein, such as ARM that binds CD38, are particularly useful for the prevention and/or treatment of conditions, disorders, or diseases associated with CD38, such as various types of cancers associated with CD 38.

Further, the present disclosure encompasses the following recognition: without wishing to be bound by any particular theory, certain immunotherapies that target targets expressing CD38 (e.g., CD38 antibodies) have one or more side effects (e.g., toxicity) due to the reduction and/or depletion of normal cells expressing CD 38. For example, as described herein, in some embodiments, a CD38 antibody, such as Daratumumab (Daratumumab), induces a reduction or depletion of immune effector cells expressing CD 38. Furthermore, the present disclosure demonstrates that the provided technology can recruit immune components and activity to CD38 expressing targets (e.g., cancer cells) to a lesser extent or without significantly reducing or depleting CD38 expressing immune effector cells as compared to CD38 antibodies such as daratumab.

In some embodiments, provided compounds (e.g., ARM) include an antibody binding moiety (universal antibody binding terminus, uABT) that can bind to antibodies of various specificities. Furthermore, such ARM can circumvent the dependence of a particular antibody population and/or adverse effects associated with individual variation of a particular antibody population. In some embodiments, the uABT can bind to an antibodyAn Fc region, and thereby can recruit antibodies with various antigen specificities, among others. In some embodiments, ABT (e.g., uABT) binds to F of IgG _CConserved positions present in the regions. In some embodiments, uABT is capable of recruiting all IgG subclasses (IgG1, IgG2, IgG3, IgG 4). In some embodiments, uABT is capable of preferentially recruiting IgG1, IgG2, and/or IgG 4. In some embodiments, the uABT binds to IgG molecules and does not bind to human IgA or IgM. In some embodiments, recruitment of antibodies (e.g., IgG subclasses) is dependent on the administered dose of ARM, and/or is independent of the level of antibodies with specific Fab regions in the individual. In some embodiments, suitable ABTs are those described in WO 2019/023501, the antibody binding portions of which (e.g., various ABTs, including uABT) are incorporated herein by reference. One of skill in the art will appreciate that a variety of antibody binding moieties are available and can be utilized in accordance with the present disclosure.

In addition, the ARM can recruit an antibody, and the recruited antibody provides one or more immune activities, e.g., via one or more antibody-mediated immune mechanisms. In some embodiments, the recruited antibody recruits and/or interacts with and/or activates an Fc receptor of an immune cell. In some embodiments, the recruited antibodies recruit and activate immune cells and inhibit and/or target diseased cells, such as cancer cells. In some embodiments, the provided agent (e.g., ARM) induces antibody-dependent effector function. In some embodiments, the provided agents (e.g., ARM) induce Complement Dependent Cytotoxicity (CDC). In some embodiments, the provided agents (e.g., ARM) induce direct cytotoxicity. In some embodiments, the provided agent (e.g., ARM) inhibits a biological function associated with steric blockade. In some embodiments, the provided agents (e.g., ARM) induce antibody-dependent cell-mediated viral inhibition (ADCVI). In some embodiments, the provided agent (e.g., ARM) induces ADCC and kills cancer cells. In some embodiments, the provided agents (e.g., ARM) induce ADCP and kill cancer cells. In some embodiments, the provided agents (e.g., ARM) induce both ADCC and ADCP.

In some embodiments, the present disclosure provides a medicament comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

optionally a linker moiety.

In some embodiments, the target binding moiety may bind CD 38. In some embodiments, the antibody binding portion can bind to two or more antibodies having different Fab regions. In some embodiments, an antibody binding moiety can bind to two or more antibodies having different antigen specificities. In some embodiments, the antibody binding portion can bind to the Fc region of various antibodies. In some embodiments, an antibody binding moiety (e.g., a universal antibody binding moiety) binds to the Fc region of an antibody. In some embodiments, an antibody binding moiety (e.g., a universal antibody binding moiety) binds to a conserved Fc region of an antibody. In some embodiments, the antibody binding moiety binds to the Fc region of an IgG antibody. In some embodiments, the antibody may still perform all or substantially all or most of its biological functions after binding to the antibody binding moiety (e.g., binding at the Fc region). For example, an antibody upon binding to an antibody binding moiety may recruit and/or activate immune cells, e.g., via interaction with various Fc receptors.

In some embodiments, the present disclosure provides compounds having general formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables are independently as defined and described herein. In some embodiments, the provided agent is a compound of formula I or a salt thereof.

In some embodiments, provided agents (e.g., compounds of formula I) are those having

A compound of structure (la), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the disclosure.

In some embodiments, provided agents are compounds of formula I-a or salts thereof. In some embodiments, the present disclosure provides a compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the disclosure. In some embodiments, provided compounds of formula I are compounds of formula I-a.

In some embodiments, provided agents are compounds of formula I-b or salts thereof. In some embodiments, the present disclosure provides a compound of formula I-b:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the disclosure. In some embodiments, provided compounds of formula I are compounds of formula I-b.

In some embodiments, the agents and compounds provided by the present disclosure and pharmaceutically acceptable compositions thereof are effective for recruiting antibodies to diseased cells, such as cancer cells. In some embodiments, the present disclosure provides compounds having general formula II:

Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. In some embodiments, the provided agent is a compound of formula II or a salt thereof. In some embodiments, a provided compound of formula I is a provided compound of formula II or a salt thereof. In some embodiments, the compound having the structure of formula I-a is a compound of formula II.

In some embodiments, the present disclosure provides compounds having general formula III:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. In some embodiments, the provided agent is a compound of formula III or a salt thereof. In some embodiments, a provided compound of formula I is a provided compound of formula III, or a salt thereof. In some embodiments, the compound having the structure of formula I-b is a compound of formula III.

The compounds of the present disclosure and pharmaceutically acceptable compositions thereof are useful in the treatment of a variety of diseases, disorders, or conditions. Such diseases, disorders, or conditions include those described herein. In some embodiments, the condition, disorder or disease is cancer.

Drawings

FIG. 1 the compounds provided recruit antibodies to target cells.

Figure 2 provided compounds can recruit antibodies to target cells and activate effector cells.

FIG. 3 provides compounds that kill target cells.

Figure 4. the provided compounds did not significantly deplete effector cells. Darunavir single antibody: 3 μ g/mL to 0.1 μ g/mL. I-9: 300nM to 10 nM. IvIG: 10. mu.g/mL.

Figure 5. the technique provided has low toxicity. A. Frequency of dead NK cells. B. Dead NK cell frequency normalized to DMSO-treated control. The CD38 ARM is I-17.

FIG. 6. the technique provided is effective in killing cancer cells. Frequency of dead SUDHL-4 cells in nk-SUDHL-4 co-cultures. B. SuDHL-4 cell death frequency in NK-SUDHL-4 co-cultures normalized to DMSO-treated controls. The CD38 ARM is I-17.

FIG. 7. techniques are provided to reduce the number of plasma cells. The CD38 ARM is I-17.

Figure 8. the provided technology has no or low levels of undesired NK cell suicide. The CD38 ARM is I-17.

FIG. 9. the technique provided is effective in reducing the number of target cells. Without intending to be limited by theory, the count of Daudi cells expressing CD38 in the intraperitoneal cavity of SCID mice served as a readout for macrophage-mediated I-17 dependent phagocytosis. From left to right: comparison; IVIG 10 mg/mouse sub-Q; i-171 mg/kg + IVIG (10 mg/mouse sub-Q); i-1710 mg/kg + IVIG (10 mg/mouse sub-Q); i-1730 mg/kg + IVIG (10 mg/mouse sub-Q); daratumab. ***: p is less than 0.001.

FIG. 10 Activity of CIML NK cells frozen in combination with I-17 and restored against MOLP-8 cells. From left to right: untreated; darunavir monoclonal antibody; cryopreserved CIML NK I-17 added to the assay; and CIML NK cryopreserved with I-17.

Detailed Description

1. General description of certain embodiments

In some embodiments, the present disclosure provides agents, such as ARM, that include a target binding moiety that can bind to CD 38. In some embodiments, provided agents (e.g., ARM) include a universal antibody binding moiety that can bind to antibodies with different Fab structures. In some embodiments, the disclosure provides agents (e.g., ARM) that include an antibody binding portion that binds to an antibody (e.g., an Fc region of an antibody), and such binding of the antibody does not interfere with one or more immune activities of the antibody, e.g., interaction with an Fc receptor (e.g., CD16a), recruitment of effector cells (e.g., NK cells (e.g., for ADCC), macrophages (e.g., for ADCP)), etc. As will be appreciated by those of skill in the art, the techniques (agents, compounds, compositions, methods, etc.) provided by the present disclosure may provide various advantages, for example, the provided techniques may utilize antibodies with various Fab regions in the immune system to avoid or minimize adverse effects of antibody changes between patient populations, may trigger and/or enhance immune activity against a target (e.g., kill a target diseased cell, such as a cancer cell), and/or have low toxicity (e.g., low complement activation, significantly less normal cells expressing CD38 (e.g., effector cells) reduction) compared to certain antibody therapeutics.

In some embodiments, the provided techniques are suitable for modulating immune activity, such as ADCC, ADCP and combinations thereof, against a target (diseased cells, foreign subject or entity, etc.) comprising CD 38. In some embodiments, the techniques of the present disclosure are suitable for recruiting antibodies to cancer cells, particularly cancer cells expressing CD 38. In some embodiments, the provided techniques are suitable for modulating ADCC against a target cell (e.g., a diseased cell, such as a cancer cell). In some embodiments, the provided techniques are suitable for modulating ADCP against a target cell (e.g., a diseased cell, such as a cancer cell). In some embodiments, provided agents can inhibit protein activity. In some embodiments, the target binding moiety is an inhibitor moiety. In some embodiments, the target binding moiety is an enzyme inhibitor moiety.

In some embodiments, the present disclosure provides a medicament comprising:

(ii) an antibody-binding moiety,

a target binding moiety that binds to CD38, and

the optional presence of a linker moiety or moieties,

wherein the antibody binding portion can bind to two or more antibodies having different Fab regions.

In some embodiments, the present disclosure provides a medicament comprising:

(ii) an antibody-binding moiety,

a target binding moiety that binds to CD38, and

the optional presence of a linker moiety or moieties,

In some embodiments, provided agents include two or more antibody binding moieties. In some embodiments, provided agents include two or more target binding moieties.

The antibody binding portion may interact with any portion of the antibody. In some embodiments, the antibody binding moiety binds to the Fc region of an antibody. In some embodiments, the antibody binding portion binds to a conserved Fc region of the antibody. In some embodiments, the antibody binding moiety binds to the Fc region of an IgG antibody. As will be appreciated by those skilled in the art, a variety of antibody binding moieties, linkers, and target binding moieties can be utilized in accordance with the present disclosure. Furthermore, as shown in the examples, in some embodiments, the present disclosure provides antibody binding moieties, linkers, and target binding moieties, and combinations thereof, that are particularly useful and effective for constructing ARM molecules to recruit antibodies to target cells and/or to trigger, generate, promote, and/or enhance immune system activity against target cells (e.g., diseased cells, e.g., cancer cells).

In some embodiments, the present disclosure provides antibody binding portions that can bind to an Fc region that binds to an Fc receptor (e.g., fcyriiia, CD16a, etc.) and/or agents that include the antibody binding portions (e.g., compounds of the various formulae described in the present disclosure, ARM molecules of the present disclosure, etc.). In some embodiments, an agent that binds to a moiety that comprises a complex of an Fc region and an Fc receptor and/or comprises the antibody binding moiety is provided. In some embodiments, the present disclosure provides a composite comprising:

a medicament, comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

the optional presence of a linker moiety or moieties,

an Fc region, and

an Fc receptor.

In some embodiments, the antibody binding portion can bind to CD38, and/or the antibody binding portion of the agent can bind to two or more antibodies having different Fab regions.

In some embodiments, the Fc region is an Fc region of an endogenous antibody of the subject. In some embodiments, the Fc region is that of an exogenous antibody. In some embodiments, the Fc region is that of the administered agent. In some embodiments, the Fc receptor belongs to a diseased cell in the subject. In some embodiments, the Fc receptor belongs to a cancer cell of the subject.

In certain embodiments, the present disclosure provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each of a and b is independently 1 to 200;

each ABT is independently an antibody binding moiety;

l is a bivalent or multivalent linker moiety linking ABT to TBT; and is

Each TBT is independently a target binding moiety.

In some embodiments, the ABT is a universal antibody binding moiety.

In some embodiments, the antibody binding portion comprises one or more amino acid residues. In some embodiments, the antibody-binding moiety is or includes a peptide moiety. In some embodiments, the antibody-binding moiety is or includes a cyclic peptide moiety. In some embodiments, such antibody binding moieties include one or more natural amino acid residues. In some embodiments, such antibody binding moieties include one or more non-natural, natural amino acid residues.

In some embodiments, the amino acid has the structure of formula a-I:

NH(R^a1)-L^a1-C(R^a2)(R^a3)-L^a2-COOH，

A-I

or a salt thereof, wherein:

R^a1、R^a2、R^a3each of which is independently-L^a-R′；

L^a1And L^a2Each of which is independently L^a；

Each L^aIndependently a covalent bond, or is selected from C₁-C₂₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₂₀A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R') ₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each-Cy-is independently an optionally substituted divalent monocyclic, bicyclic, or polycyclic group, wherein each monocyclic ring is independently selected from: c_3-20A cycloaliphatic ring; c_6-20An aryl ring; a 5-to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3 to 20 membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Each R is independently-H, or an optionally substituted group selected from: c_1-30An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-30A heteroaliphatic group; c_6-30An aryl group; c_6-30An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-30An aryl heteroaliphatic group; a 5-to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3-to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

Optionally and independently, two R groups together form a covalent bond, or:

two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or

Two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, the amino acid analogs are compounds in which the amino group and/or the carboxylic acid group are independently replaced with an optionally substituted aliphatic or heteroaliphatic moiety. As will be appreciated by those of skill in the art, many amino acid analogs that mimic the structure, properties, and/or function of an amino acid are described in the art and can be utilized in accordance with the present disclosure.

In some embodiments, the antibody-binding moiety is a cyclic peptide moiety. In some embodiments, the present disclosure provides a compound of formula I-a:

or a salt thereof, wherein:

each Xaa is independently a residue of an amino acid or amino acid analog;

t is 0 to 50;

z is 1 to 50;

l is a linker moiety;

TBT is a target binding moiety;

each R^cIndependently is-L^a-R′；

Each of a and b is independently 1 to 200;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Optionally and independently, two R groups together form a covalent bond, or:

In some embodiments, a is 1. In some embodiments, b is 1. In some embodiments, a is 1 and b is 1, and the compounds of formula I-a have the following structure:

in some embodiments, each residue (e.g., Xaa) is independently a residue of an amino acid or an amino acid analog, wherein the amino acid or the amino acid analog has H-L^a1-L^a1-C(R^a2)(R^a3)-L^a2-L^a2-H structure or a salt thereof. In some embodiments, the amino acid has NH (R)^a1)-L^a1-C(R^a2)(R^a3)-L^a2-COOH structure orA salt thereof. In some embodiments, the amino acid analog has H-L^a1-L^a1-C(R^a2)(R^a3)-L^a2-L^a2-H structure or a salt thereof. In some embodiments, in such amino acid analogs, the first-L^a1- (bonded to-H in said formula) other than-N (R)^a1) - (e.g. being optionally substituted divalent C)_1-6Aliphatic group). In some embodiments, in H-L^a1-L^a1-in, -L^a1-L^a1-is bonded to-H via an atom other than nitrogen. In some embodiments, at-L^a2-L^a2in-H, -L^a2-L^a2-is not bonded to-H via-C (O) O-. In some embodiments, each residue (e.g., each Xaa in formula I-a) is independently a residue of an amino acid having the structure of formula A-I.

In some embodiments, each Xaa independently has-L^a1-L^a1-C(R^a2)(R^a3)-L^a2-L^a2-a structure. In some embodiments, each Xaa independently has-L^aX1-L^a1-C(R^a2)(R^a3)-L^a2-L^aX2-structure wherein L^aX1Is optionally substituted-NH-, optionally substituted-CH₂-、-N(R^a1) -or-S-, L^aX2Is optionally substituted-NH-, optionally substituted-CH₂-、-N(R^a1) -or-S-, and each other variable is independently as described herein. In some embodiments, L^aX1Is optionally substituted-NH-or-N (R)^a1) -. In some embodiments, L^aX1Is optionally substituted-CH₂-or-S-. In some embodiments, L^aX2Is optionally substituted-NH-, optionally substituted-CH₂-、-N(R^a1) -or-S-. In some embodiments, optionally substituted-CH₂is-C (O) -. In some embodiments, optionally substituted-CH₂-is not-C (O) -. In some embodiments, L^aX2is-C (O) -. In some embodiments, each Xaa independently has-N (R)^a1)-L^a1-C(R^a2)(R^a3)-L^a2-CO-structure.

In many embodimentsTwo or more residues (e.g., two or more Xaa residues) are linked together to form one or more cyclic structures. For example, various compounds in table 1 include attached residues. The residue may optionally be linked via a linker (e.g., L) at any suitable position^T) And (4) connecting. For example, a bond between two residues may link each residue independently at its N-terminus, C-terminus, a point on the backbone, or a point on the side chain, etc. In some embodiments, for example, two or more side chains of a residue in a compound of formula I-a (e.g., R of one amino acid residue) ^a2Or R^a3With another amino acid residue^a2Or R^a3) Optionally together forming a bridge (e.g., in the various compounds in table 1, etc.), for example, in some embodiments, two cysteine residues form an-S-bridge as is commonly observed in native proteins. In some embodiments, the formed bridge has L^bStructure of, wherein L^bIs L as described in this disclosure^a. In some embodiments, L^bEach end of (a) is independently attached to a backbone atom of a cyclic peptide (e.g., - (Xaa) in formula I-a_zThe ring atoms of the ring formed). In some embodiments, L^bIncluding the R group (e.g. when L^bIs represented by the formula (II) or (III)₂-or-N (R) -when substituted), wherein the R group is substituted with an R group attached to the backbone atom (e.g. R when R is R)^a1、R^a2、R^a3Etc.) and their intermediate atoms together form a ring. In some embodiments, L^bTo the ring via the side chain of an amino acid residue (e.g. Xaa in formula I-a), e.g. by- (Xaa) in formula I-a_z-the ring formed. In some embodiments, such side chains include amino groups or carboxylic acid groups. In some embodiments, L^TIs L as described herein^b. In some embodiments, a key (e.g., L)^bOr L^T) Linking the side chain of the residue to the N-terminus or C-terminus. In some embodiments, the side chain linking the residue to an amino group. In some embodiments, the side chain linking the residue to the α -amino group. In some embodiments, as illustrated herein, a key (e.g., L) ^bOr L^T) is-CH₂-C (O) -. At one endIn some embodiments, -CH₂-S-bonded to a side chain, e.g. to a cysteine residue, and-c (o) -bonded to an amino group, e.g. an alpha-amino group of a residue. In some embodiments, a key (e.g., L)^bOr L^T) Is optionally substituted-CH₂-S-CH₂-C (O) -NH-, wherein each end is bonded to the α -carbon of the residue. In some embodiments, -NH-belongs to the alpha-amino group of a residue (e.g., the N-terminal residue).

In some embodiments of the present invention, the,

is an antibody-binding moiety: (

Binding to an antibody). In some embodiments of the present invention, the,

is a universal antibody binding moiety. In some embodiments of the present invention, the,

is a universal antibody binding moiety that can bind to antibodies having different Fab regions. In some embodiments of the present invention, the,

is a universal antibody binding moiety that can bind to an Fc region. In some embodiments, the antibody-binding moiety, for example, has

The universal antibody binding portion of the structure can bind to an Fc region that binds to an Fc receptor. In some embodiments, the antibody-binding moiety, for example, has

The antibody-binding portion of the structure has the following structure:

in some embodiments of the present invention, the,

has the following structure:

in certain embodiments, the present disclosure provides a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R¹、R³And R⁵Each of which is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:

R¹and R¹' optionally together with its intervening carbon atoms form a 3-to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³and R³' optionally together with its intervening carbon atoms form a 3-to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

r bound to the same carbon atom⁵Group and R⁵' the group optionally together with its intervening carbon atoms forms a 3-to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or has 1 to 2 hetero atoms independently selected from nitrogen, oxygen or sulfur An atomic 3 to 8 membered saturated or partially unsaturated spirocyclic heterocycle; or

Two R⁵The radicals optionally forming C together with their intermediate atoms_1-10An optionally substituted divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally substituted by-S-, -SS-, -N (R) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) N (R) -, -N (R) C (O) -, -S (O)₂-or-Cy¹-substitution, wherein each-Cy¹-independently is a 5-to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R¹′、R³' and R⁵Each of' is independently hydrogen or optionally substituted C_1-3An aliphatic group;

R²、R⁴and R⁶Each of which is independently hydrogen or optionally substituted C_1-4An aliphatic group, or:

R²and R¹Optionally together with their intermediate atoms, form a 4-to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R⁴and R³Optionally together with their intermediate atoms, form a 4-to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

R⁶Group and its adjacent R⁵The groups optionally together with their intermediate atoms form a 4-to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹To connect to

A trivalent linker moiety of (a);

L²is a covalent bond or C_1-30An optionally substituted divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 10 methylene units of said chain are independently and optionally substituted by-S-, -N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-C(O)N(R)-、-N(R)C(O)-、-S(O)-、-S(O)₂-、

or-Cy¹-substitution, wherein each-Cy¹-independently is a 5-to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

TBT is a target binding moiety; and is

Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, the antibody-binding moiety is or includes a peptide moiety. In some embodiments, the present disclosure provides a compound having the structure of formula I-b:

or a salt thereof, wherein:

each Xaa is independently a residue of an amino acid or amino acid analog;

each z is independently 1 to 50;

each L is independently a linker moiety;

the TBT is the binding moiety of the target,

each R^cIndependently is-L^a-R′；

Each of a1 and a2 is independently 0 or 1, wherein at least one of a1 and a2 is not 0;

each of a and b is independently 1 to 200;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Optionally and independently, two R groups together form a covalent bond, or:

In some embodiments, a1 is 1. In some embodiments, a2 is 1. In some embodiments, b is 1. In some embodiments, the compounds of formula I-b have the following structure:

in some embodiments, the compounds of formula I-b have the following structure:

in some embodiments, the compounds of formula I-b have the following structure:

in some embodiments, the compounds of formula I-b have the following structure:

in some embodiments, each residue (e.g., each Xaa in formulas I-a, I-b, etc.) is independently a residue of an amino acid having the structure of formula A-I. In some embodiments, each Xaa independently has-N (R)^a1)-L^a1-C(R^a2)(R^a3)-L^a2-CO-structure. In some embodiments, for example, two or more side chains of an amino acid residue (e.g., R of an amino acid residue) in a compound of formula I-a^a2Or R^a3With another amino acid residue^a2Or R^a3) Optionally forming a bridge (e.g., the various compounds in table 1) together, e.g., in some embodiments, two cysteine residues form an-S-bridge as is commonly observed in native proteins. In some embodiments, the formed bridge has L ^bStructure of, wherein L^bIs L as described in this disclosure^a. In some embodiments, L^bEach end of (a) is independently attached to a backbone atom of a cyclic peptide (e.g., - (Xaa) in formula I-a_zThe ring atoms of the ring formed). In some embodiments, L^bIncluding the R group (e.g. when L^bIs represented by the formula (II) or (III)₂-or-N (R) -when substituted), wherein the R group is substituted with an R group attached to the backbone atom (e.g. R when R is R)^a1、R^a2、R^a3Etc.) and their intermediate atoms together form a ring. In some embodiments, L^bVia side chains of amino acid residues (e.g. of formula I)Xaa in-a) is attached to the ring, e.g. by- (Xaa) in formula I-b_z-the ring formed. In some embodiments, such side chains include amino groups or carboxylic acid groups.

In some embodiments, R^c- (Xaa) z-is an antibody binding moiety (R)^c- (Xaa) z-H binding to an antibody). In some embodiments, R^c- (Xaa) z-is a universal antibody binding moiety. In some embodiments, R^c- (Xaa) z-is a universal antibody binding moiety that can bind to antibodies having different Fab regions. In some embodiments, R^c- (Xaa) z-is a universal antibody binding moiety that can bind to an Fc region. In some embodiments, the antibody binding moiety, e.g., with R^cThe generic antibody binding portion of the- (Xaa) z-structure can bind to an Fc region that binds to an Fc receptor. In some embodiments, R ^c- (Xaa) z-has the structure:

in some embodiments, R^c- (Xaa) z-L-has the structure:

in certain embodiments, the present disclosure provides a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R⁷each of which is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:

r bound to the same carbon atom⁷Group and R⁷' the group optionally together with its intervening carbon atoms forms a 3-to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-to 8-membered optionally substituted saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R⁷each of' is independently hydrogen or optionally substituted C_1-3An aliphatic group;

R⁸Each of which is independently hydrogen or optionally substituted C_1-4An aliphatic group, or:

R⁸group and R adjacent thereto⁷The groups optionally together with their intermediate atoms form a 4-to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R⁹is hydrogen, optionally substituted C_1-3Aliphatic radical or-C (O) - (optionally substituted C)_1-3Aliphatic groups);

L³to connect to

A divalent linker group to TBT;

TBT is a target binding moiety; and is

o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

2. Definition of

The compounds of the present disclosure include compounds generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this disclosure, chemical elements are identified according to the periodic table of elements, CAS version, Handbook of Chemistry and Physics, 75 th edition. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books (University Science Books), sudox (sautalito): 1999 and "March's Advanced Organic Chemistry", 5 th edition, editor: smith, m.b. and March, j., John Wiley parent-child publishing company (John Wiley & Sons), new york: 2001.

As used herein in this disclosure, unless the context clearly dictates otherwise, (i) the terms "a" and (an) "are to be understood as meaning" at least one "; (ii) the term "or" may be understood to mean "and/or"; (iii) the terms "comprising," including, "" containing, "" whether used with "or without limitation," and "containing" whether used with "or without limitation," are understood to encompass the recited components or steps, whether presented alone or with one or more additional components or steps; (iv) the term "another" can be understood to mean at least an additional/second one or more; (v) the terms "about" and "approximately" are understood to allow for a standard deviation as understood by those skilled in the art; and (vi) when ranges are provided, the endpoints are included. Unless otherwise specified, the compounds described herein may be provided and/or utilized in the form of a salt, specifically a pharmaceutically acceptable salt.

Aliphatic group: as used herein, "aliphatic group" means a straight-chain (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is fully saturated or contains one or more units of unsaturation, but which is not aromatic, or a combination thereof. In some embodiments, the aliphatic group contains 1 to 50 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 20 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 10 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 9 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 8 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 7 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 6 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and mixtures thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

Alkenyl: as used herein, the term "alkenyl" refers to an aliphatic group as defined herein having one or more double bonds.

Alkyl groups: as used herein, the term "alkyl" has its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups (alicyclic groups), cycloalkyl groups substituted with alkyl groups, and alkyl groups substituted with cycloalkyl groups. In some embodiments, the alkyl group has 1 to 100 carbon atoms. In certain embodiments, the straight or branched chain alkyl group has about 1 to 20 carbon atoms in its backbone (e.g., straight is C)₁-C₂₀Branched chain is C₂-C₂₀) And alternatively about 1 to 10. In some embodiments, cycloalkyl rings have about 3 to 10 carbon atoms in their ring structure, wherein such rings are monocyclic, bicyclic, or polycyclic, and alternatively have about 5, 6, or 7 carbon atoms in the ring structure. In some embodiments, the alkyl group can be a lower alkyl group, wherein the lower alkyl group includes 1 to 4 carbon atoms (e.g., straight chain lower alkyl is C)₁-C₄)。

Alkynyl: as used herein, the term "alkynyl" refers to an aliphatic group as defined herein having one or more triple bonds.

Aryl: as used herein, the term "aryl", alone or as used as part of a larger moiety in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic, bicyclic, or polycyclic ring system having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, aryl is a monocyclic, bicyclic, or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, aryl is biaryl. The term "aryl" is used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimide, phenanthridinyl, or tetrahydronaphthyl, and the like.

A cycloaliphatic group: the terms "cycloaliphatic", "carbocycle", "carbocyclyl", and "carbocycle" are used interchangeably and, as used herein, refer to a saturated or partially unsaturated, but non-aromatic, cycloaliphatic monocyclic, bicyclic, or polycyclic ring system as described herein, having from 3 to 30 ring members, unless otherwise specified. Cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloaliphatic group has from 3 to 6 carbon atoms. In some embodiments, the cycloaliphatic group is saturated and is cycloalkyl. The term "cycloaliphatic" may also encompass an aliphatic ring fused to one or more aromatic or non-aromatic rings (e.g., decahydronaphthyl or tetrahydronaphthyl). In some embodiments, the cycloaliphatic group is bicyclic. In some embodiments, the cycloaliphatic group is tricyclic. In some embodiments, the cycloaliphatic group is polycyclic. In some embodiments, "cycloaliphatic" refers to a fully saturated or non-aromatic C containing one or more units of unsaturation with a single point of attachment to the rest of the molecule ₃-C₆Monocyclic hydrocarbon or C₈-C₁₀Bicyclic or polycyclic hydrocarbons, or C, fully saturated or containing one or more units of unsaturation, but not aromatic, having a single point of attachment to the rest of the molecule₉-C₁₆Polycyclic hydrocarbons.

The administration scheme is as follows: as used herein, a "dosing regimen" or "treatment regimen" refers to a group of unit doses (typically more than one) that are administered individually to a subject, typically at spaced apart time periods. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen comprises a plurality of doses, each of which is spaced apart from each other for a period of time of the same length; in some embodiments, the dosing regimen comprises a plurality of doses and at least two different time periods spaced apart by an individual dose. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose in an amount of a first dose, followed by one or more additional doses in an amount of a second dose that is different from the amount of the first dose. In some embodiments, the dosing regimen comprises a first dose in the amount of the first dose followed by one or more additional doses in the amount of a second dose that is the same as the amount of the first dose.

Heteroaliphatic group: as used herein, the term "heteroaliphatic" has its ordinary meaning in the art, and refers to an aliphatic group as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). In some embodiments, selected from C, CH₂And CH₃Independently by one or more heteroatoms (including oxidized and/or substituted forms thereof). In some embodiments, the heteroaliphatic group is a heteroalkyl group. In some embodiments, the heteroaliphatic group is a heteroalkenyl group.

Heteroalkyl group: as used herein, the term "heteroalkyl" has its ordinary meaning in the art and refers to an alkyl group as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly (ethylene glycol) -, amino substituted with alkyl, tetrahydrofuranyl, piperidinyl, morpholinyl, and the like.

Heteroaryl group: as used herein, the terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to monocyclic, bicyclic, or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, heteroaryl is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic, or polycyclic), in some

embodiments

5, 6, 9, or 10 ring atoms. In some embodiments, heteroaryl groups have 6, 10, or 14 pi electrons in common in the ring array; and has one to five heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, heteroaryl is a heterobiaryl, such as bipyridyl and the like. As used herein, the terms "heteroaryl" and "heteroar-" also encompass groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the linking group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2, 3-b ] -1, 4-oxazin-3 (4H) -one. Heteroaryl groups can be monocyclic, bicyclic, or polycyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms comprises an optionally substituted ring. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

Heteroatom: as used herein, the term "heteroatom" means an atom that is not carbon or hydrogen. In some embodiments, the heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including various forms of such atoms, e.g., oxidized forms (e.g., of nitrogen, sulfur, phosphorus, or silicon), quaternized forms of basic nitrogen, or a heterocyclic ring (e.g., N, as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺(e.g., in N-substituted pyrrolidinyl), and the like). In some embodiments, the heteroatom is oxygen, sulfur, or nitrogen.

Heterocyclic ring: as used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably as used herein and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3 to 30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, heterocyclyl is a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and that has one or more (preferably one to four) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used in conjunction with a ring atom of a heterocyclic ring includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or ⁺NR (as in N-substituted pyrrolidinyl). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, oxazepine, thiazepine, morpholinyl, and quinuclidinyl. The terms "heterocycle (heterocyclic)", "heterocyclyl ring (heterocyclo)ycycling), "heterocyclyl group," "heterocyclic moiety" and "heterocyclic radial" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclic group may be monocyclic, bicyclic or polycyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

Lower alkyl group: the term "lower alkyl" refers to C_1-4Straight-chain or branched-chain alkyl. Examples of lower alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

Lower haloalkyl: the term "lower haloalkyl" refers to C substituted with one or more halogen atoms_1-4Straight-chain or branched-chain alkyl.

Optionally substituted: as described herein, the compounds of the present disclosure may contain optionally substituted and/or substituted moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. In some embodiments, the optionally substituted group is unsubstituted. The combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" means that the compound is not substantially altered when subjected to conditions that allow its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein. Certain substituents are described below.

Suitable monovalent substitutions on substitutable atoms, e.g. suitable carbon atomsIndependently, the radicals are halogen; - (CH)₂)_0- ₄R^；-(CH₂)_0-4OR^；-O(CH₂)_0-4R^o；-O-(CH₂)_0-4C(O)OR^o；-(CH₂)_0-4CH(OR^)₂(ii) a Can be substituted by R^oSubstituted- (CH)₂)_0-4Ph; can be substituted by R^oSubstituted- (CH)₂)_0-4O(CH₂)_0-1Ph; can be substituted by R^osubstituted-CH ═ CHPh; can be substituted by R^oSubstituted- (CH)₂)_0-4O(CH₂)_0-1-a pyridyl group; -NO₂；-CN；-N₃；-(CH₂)_0-4N(R^)₂；-(CH₂)_0-4N(R^)C(O)R^；-N(R^)C(S)R^；-(CH₂)_0-4N(R^)C(O)NR^₂；-N(R^)C(S)NR^₂；-(CH₂)_0-4N(R^)C(O)OR^；-N(R^)N(R^)C(O)R^；-N(R^)N(R^)C(O)NR^₂；-N(R^)N(R^)C(O)OR^；-(CH₂)_0-4C(O)R^；-C(S)R^；-(CH₂)_0-4C(O)OR^；-(CH₂)_0-4C(O)SR^；-(CH₂)_0-4C(O)OSiR^₃；-(CH₂)_0-4OC(O)R^；-OC(O)(CH₂)_0-4SR^o；-SC(S)SR^o；-(CH₂)_0-4SC(O)R^；-(CH₂)_0-4C(O)NR^₂；-C(S)NR^₂；-C(S)SR^o；-(CH₂)_0-4OC(O)NR^₂；-C(O)N(OR^)R^；-C(O)C(O)R^；-C(O)CH₂C(O)R^；-C(NOR^)R^；-(CH₂)_0-4SSR^；-(CH₂)_0-4S(O)₂R^；-(CH₂)_0-4S(O)₂OR^；-(CH₂)_0-4OS(O)₂R^；-S(O)₂NR^₂；-(CH₂)_0-4S(O)R^；-N(R^)S(O)₂NR^₂；-N(R^)S(O)₂R^；-N(OR^)R^；-C(NH)NR^₂；-Si(R^)₃；-OSi(R^)₃；-B(R^)₂；-OB(R^)₂；-OB(OR^)₂；-P(R^)₂；-P(OR^)₂；-P(R^)(OR^)；-OP(R^)₂；-OP(OR^)₂；-OP(R^)(OR^)；-P(O)(R^)₂；-P(O)(OR^)₂；-OP(O)(R^)₂；-OP(O)(OR^)₂；-OP(O)(OR^)(SR^)；-SP(O)(R^)₂；-SP(O)(OR^)₂；-N(R^)P(O)(R^)₂；-N(R^)P(O)(OR^)₂；-P(R^)₂[B(R^)₃]；-P(OR^)₂[B(R^)₃]；-OP(R^)₂[B(R^)₃]；-OP(OR^)₂[B(R^)₃]；-(C_1-4Straight or branched alkylene) O-N (R ^)₂(ii) a Or- (C)_1-4Straight or branched chain alkylene) C (O) O-N (R ^ R)₂Wherein each R ^ can be substituted as defined herein and independently is: hydrogen, C_1-20Aliphatic radical, C having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus_1-20Heteroaliphatic group, -CH₂-(C_6-14Aryl group, -O (CH)₂)_0-1(C_6-14Aryl group), -CH₂- (5-to 14-membered heteroaryl ring), a 5-to 20-membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus; or in addition to the above definitions, two independently occurring R ^ s together with their intervening atoms form a 5 to 20 membered, monocyclic, bicyclic, or polycyclic saturated, partially unsaturated, or aryl ring having 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus, which may be substituted as defined below.

Suitable monovalent substituents on R ^ (or rings formed by combining two independently occurring R ^ with their intervening atoms) are independently halogen, - (CH) ₂)_0-2R^·- (halogeno radical R)^·)、-(CH₂)_0-2OH、-(CH₂)_0-2OR^·、-(CH₂)_0- ₂CH(OR^·)₂-O (halo R)^·)、-CN、-N₃、-(CH₂)_0-2C(O)R^·、-(CH₂)_0-2C(O)OH、-(CH₂)_0-2C(O)OR^·、-(CH₂)_0-2SR^·、-(CH₂)_0-2SH、-(CH₂)_0-2NH₂、-(CH₂)_0-2NHR^·、-(CH₂)_0-2NR^· ₂、-NO₂、-SiR^· ₃、-OSiR^· ₃、-C(O)SR^·、-(C_1-4Straight OR branched chain alkylene) C (O) OR^·or-SSR^·Wherein each R^·Unsubstituted or substituted with only one or more halogens when preceded by a "halo" group and is independently selected from: c_1-4Aliphatic radical, -CH₂Ph，-O(CH₂)_0-1Ph, or a 5 to 6 membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on the saturated carbon atom of R ^ include ═ O and ═ S.

For example, suitable divalent substituents on suitable carbon atoms are independently the following: is one of O, S and NNR^* ₂、＝NNHC(O)R^*、＝NNHC(O)OR^*、＝NNHS(O)₂R^*、＝NR^*、＝NOR^*、-O(C(R^* ₂))_2-3O-or-S (C (R)^* ₂))_2-3S-, wherein each independently occurs R^*Selected from: hydrogen, C which may be substituted as defined below_1-6An aliphatic group, or an unsubstituted 5-to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents bound to adjacent substitutable carbons of the "optionally substituted" group include: -O (CR)^* ₂)_2-3O-, in which each occurrence of R is independent^*Selected from: hydrogen, C which may be substituted as defined below_1-6An aliphatic group, and an unsubstituted 5-to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

R^*Suitable substituents on the aliphatic radical of (a) are independently halogen, -R^·- (halogeno radical R)^·)、-OH、-OR^·-O (halo R)^·)、-CN、-C(O)OH、-C(O)OR^·、-NH₂、-NHR^·、-NR^· ₂Or-NO₂Wherein each R^·Unsubstituted or substituted with only one or more halogens when preceded by a "halo" group and independently: c_1-4Aliphatic radical, -CH₂Ph，-O(CH₂)_0-1Ph, or a 5 to 6 membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, suitable substituents on the substitutable nitrogen are independently

Or

Wherein each one of

Independently are: hydrogen, C which may be substituted as defined below_1-6An aliphatic group, unsubstituted-OPh, or an unsubstituted 5-to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or, in addition to the above definitions, two independently

Together with their central atoms, form an unsubstituted 3-to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

Suitable substituents on the aliphatic radical of (a) are independently halogen, -R^·- (halogeno radical R)^·)、-OH、-OR^·-O (halo R)^·)、-CN、-C(O)OH、-C(O)OR^·、-NH₂、-NHR^·、-NR^· ₂or-NO₂Wherein each R^·Is not taken outSubstituted or when the foregoing is "halo" is substituted with only one or more halogens and independently is: c _1-4Aliphatic radical, -CH₂Ph，-O(CH₂)_0-1Ph, or a 5 to 6 membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Partial unsaturation: as used herein, the term "partially unsaturated" refers to a cyclic moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to encompass aryl or heteroaryl moieties as defined herein.

The pharmaceutical composition comprises: as used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a treatment regimen in a unit dose amount suitable for administration that, when administered to a relevant population, exhibits a statistically significant probability of achieving the intended therapeutic effect. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including pharmaceutical compositions suitable for: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets targeted for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example by subcutaneous, intramuscular, intravenous or epidural injection, as for example a sterile solution or suspension or a sustained release formulation; topical application, such as creams, ointments or controlled release patches or sprays applied to the skin, lungs or oral cavity; intravaginally or intrarectally, e.g., as a pessary, cream or foam; under the tongue; eye passing; percutaneous; or nasal, pulmonary, and other mucosal surfaces.

Pharmaceutically acceptable: as used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

A pharmaceutically acceptable carrier: as used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ or portion of the body to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; no pyrogen water; isotonic saline; ringer's solution (Ringer's solution); ethanol; a pH buffer solution; polyesters, polycarbonates and/or polyanhydrides; as well as other non-toxic compatible materials employed in pharmaceutical formulations.

Pharmaceutically acceptable salts: as used herein, the term "pharmaceutically acceptable salt" refers to salts of such compounds that are suitable for use in a pharmaceutical setting, i.e., salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, s.m. berge et al, journal of pharmaceutical Sciences (j. pharmaceutical Sciences), 66: pharmaceutically acceptable salts are described in detail in 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups with inorganic or organic acidsSalts formed with acids, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods used in the art, such as ion exchange methods. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoate, pectinates, persulfates, 3-phenylpropionates, persulfates, salts of alginic acid, salts of citric acid, salts of fumaric acid, salts of gluconic acid, salts of fumaric acid, salts of bifunctional salts of fumaric acid, and salts of maleic acid, salts of bifunctional salts of maleic acid, salts of bifunctional salts of maleic acid, and salts of bifunctional acid, and salts of bifunctional acid, and derivatives of bifunctional salts of bifunctional acid, and of bifunctional salts of bifunctional acid, and use of bifunctional salts of bifunctional acids, and use of bifunctional salts of bifunctional acids, and use of bifunctional salts of bifunctional acids, and of bifunctional salts of bifunctional, Phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. In some embodiments, provided compounds include one or more acidic groups, and the pharmaceutically acceptable salt is an alkali metal salt, alkaline earth metal salt, or ammonium salt (e.g., n (r)) ₃Wherein each R is independently defined and described in the present disclosure). Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl groups having 1 to 6 carbon atoms, sulfonate, and arylsulfonate. In some embodiments, provided compounds include more than one acidA sex group. In some embodiments, a pharmaceutically acceptable salt or, generally, a salt of such a compound includes two or more cations that may be the same or different. In some embodiments, in pharmaceutically acceptable salts (or salts in general), all of the ionizable hydrogens in the acidic groups (e.g., in aqueous solution having a pKa of no more than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, no more than about 7; in some embodiments, no more than about 6; in some embodiments, no more than about 5; in some embodiments, no more than about 4; in some embodiments, no more than about 3) are replaced with cations.

Protecting groups: as used herein, the term "Protecting group" is well known in the art and includes Protecting Groups described in detail in Organic Synthesis (Protecting Groups in Organic Synthesis), t.w.greene and p.g.m.wuts, 3 rd edition, john wili father publications, 1999, the entire contents of which are incorporated herein by reference. Also included are protecting groups specifically adapted for nucleoside and nucleotide chemistries as described in the Current Nucleic Acid Chemistry protocol (Current Protocols in Nucleic Acid Chemistry) edited by Serge l.beaucage et al 06/2012, the entire contents of chapter 2 of which are incorporated herein by reference. Suitable amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo) fluorenylmethyl carbamate, 9- (2, 7-dibromo) fluorenylmethyl carbamate, 2, 7-di-tert-butyl- [9- (10, 10-dioxo-10, 10, 10, 10-tetrahydrothioxanthyl) ] methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl methyl carbamate (Phenoc), 2, 2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1-carbamic, 1-dimethyl-2-haloethyl carbamate, 1-dimethyl-2, 2-dibromoethyl carbamate (DB-t-BOC), 1-dimethyl-2, 2, 2-trichloroethyl carbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethyl carbamate (Bpoc), 1- (3, 5-di-tert-butylphenyl) -1-methylethyl carbamate (t-Bumeoc), 2- (2 '-and 4' -pyridyl) ethyl carbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), Allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2, 4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthracylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2- (p-toluenesulfonyl) ethyl carbamate, methyl carbamate, ethyl carbamate, N-butyl acetate, N-butyl, N-butyl, N-butyl, N-butyl, [2- (1, 3-dithianyl) ] methyl carbamate (Dmoc), 4-methylthiophene carbamate (Mtpc), 2, 4-dimethylthienyl carbamate (Bmpc), 2-phosphonium ethyl carbamate (Peoc), 2-triphenylphosphonium isopropyl carbamate (Ppoc), 1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyoxyboro) benzyl carbamate, 5-benzisoxazolyl methyl carbamate, 2- (trifluoromethyl) -6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5-dimethoxybenzyl carbamate, o-nitrophenyl carbamate, 3, 4-dimethoxy-6-nitrobenzyl carbamate, 2- (trifluoromethyl) -6-chromonyl methyl carbamate (Tcroc), Phenyl (o-nitrophenyl) methyl carbamate, phenothiazinyl- (10) -carbonyl derivative, N ' -p-toluenesulfonylaminocarbonyl derivative, N ' -phenylaminothiocarbonyl derivative, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2-dimethoxycarbonylvinyl carbamate, o- (N, N-dimethylcarboxamido) benzyl carbamate, 1-dimethyl-3- (N, N-dimethylcarboxamido) propyl carbamate, 1-dimethylpropynyl carbamate, di- (2-pyridyl) methyl carbamate, di- (N, N-methyl) methyl carbamate, di- (N, N-methyl) carbamate, di- (2-methyl) carbamate, di- (N, N-methyl) carbamate, di (N-methyl) carbamate, N ' -phenyl-methyl) carbamate, di (N-methyl) carbamate, di (2, N-methyl) carbamate, di (N, di-methyl) carbamate, di-methyl, di-or di-methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinite carbamate, p- (p' -methoxyphenylazo) benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1- (3, 5-dimethoxyphenyl) ethyl carbamate, 1-methyl-1- (p-phenylazophenyl) ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzyl carbamate, p-methyl-1- (4-pyridyl) ethyl carbamate, p-methyl-1- (phenylazo) benzyl carbamate, p-methyl-1- (3, 5-dimethoxyphenyl) carbamate, p-methyl-1- (p-phenylazophenyl) ethyl carbamate, n-butyl-methyl-1-cyclopropylmethyl carbamate, n-methyl-1- (4-pyridyl) ethyl carbamate, p-methyl-phenylazo) ethyl carbamate, n-methyl-1-ethyl carbamate, n-methyl-1-methyl-carbamate, n-methyl-1-methyl-carbamate, p-methyl-1-methyl-2-methyl-carbamate, p-methyl-2-methyl-carbamate, and-methyl-ethyl, or-methyl-2-ethyl, or-methyl-ethyl-methyl-ethyl, or-ethyl-methyl-ethyl, or-methyl-ethyl-methyl-ethyl, or-methyl-ethyl carbamate, or-ethyl-methyl-2-methyl-2-ethyl, or-methyl-ethyl, or-methyl-ethyl, or-methyl-or-methyl-or-methyl-ethyl, or-methyl-or-ethyl, or-p-or-p-, 2, 4, 6-tri-tert-butylphenyl carbamate, 4- (trimethylammonium) benzyl carbamate, 2, 4, 6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenyloxyacetamide, acetoacetamide, (N' -dithiobenzyloxycarbonylamino) acetamide, 3- (p-hydroxyphenyl) propionamide, 3- (o-nitrophenyl) propionamide, 2-methyl-2- (o-nitrophenyloxy) propionamide, 2-methyl-2- (o-phenylazoylphenoxy) propionamide, N-phenylthiocarbonylamino-methyl-3- (p-hydroxyphenyl) propionamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-phenylacetamide, o-nitrophenyl-acetamide, o-2-methyl-2- (o-phenylazoyl-phenoxy) propionamide, N-phenylazoyl-propionamide, N-phenyl-3- (p-phenylazoyl) -propionamide, N-phenylazoyl-propionamide, N-phenylazophenoxy) amide, N-propionamide, N-substituted phenyl-acylamide, N-substituted acylamino-substituted acylamino-substituted acylamino, and their derivatives, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, o- (benzoyloxymethyl) benzamide, 4, 5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2, 3-diphenylmaleimide, N-2, 5-dimethylpyrrole, N-1, 1, 4, 4-tetramethyldiazacyclopentane adduct (STABASE), 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-one, 5-substituted 1, 3-benzhydryl-1, 3, 5-triazacyclohex-2-one, 1-substituted 3, 5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2- (trimethylsilyl) ethoxy ] methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) amine, quaternary ammonium salts, N-benzylamine, N-bis (4-methoxyphenyl) methylamine, N-5-dibenzocycloheptylamine, N-triphenylmethylamine (Tr), N- [ (4-methoxyphenyl) diphenylmethyl ] amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2, 7-dichloro-9-fluorenylmethylidene amine, N-ferrocenylmethylamino (Fcm), N-2-pyridylmethylamino N '-oxide, N-1, 1-dimethylthiomethyl amine, N-benzylidene amine, N-p-methoxybenzylidene amine, N-diphenylmethylidene amine, N- [ (2-pyridyl) mesityl ] methylidene amine, N- (N', N '-dimethylaminomethylene) amine, N' -isopropylidene diamine, N-p-nitrophenylylidene amine, N-salicylidene amine, N-5-chlorosalicylidene amine, N- (5-chloro-2-hydroxyphenyl) phenylmethylidene amine, N-cyclohexylidene amine, N-tolylidene, N- (5, 5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivatives, N-diphenylboronic acid derivatives, N- [ phenyl (chromium or tungsten pentacarbonyl) carbonyl ] amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthiophosphamides (Mpt), diphenylphosphinamides (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfinamides (Nps), 2, 4-dinitrobenzenesulfenamides, pentachlorobenzenesulfinamides, 2-nitro-4-methoxybenzenesulfinamides, triphenylmethylsulfinamides, 3-nitropyridinesulfinamides (Npys), P-toluenesulfonamide (Ts), benzenesulfonamide, 2, 3, 6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2, 4, 6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2, 3, 5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2, 4, 6-trimethylbenzenesulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2, 5, 7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4', 8' -Dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and benzoylmethanesulfonamide.

Suitable protected carboxylic acids further include, but are not limited to, carboxylic acids protected by silane groups, alkyl groups, alkenyl groups, aryl groups, and arylalkyl groups. Examples of suitable silane groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, trityl, tert-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl groups (e.g., p-methoxybenzyl (MPM), 3, 4-dimethoxybenzyl, O-nitrobenzyl, p-halophenyl-methyl, 2, 6-dichlorobenzyl, p-cyanobenzyl) as well as 2-picolyl and 4-picolyl.

Suitable hydroxy protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), Benzyloxymethyl (BOM), p-methoxyphenylmethoxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), Guaiacolmethyl (GUM), tert-butoxymethyl, 4-Pentenyloxymethyl (POM), silanyloxymethyl, 2-methoxyethoxymethyl (MEM), 2, 2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-Methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperidin-4-yl (CTMP), 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7, 7 a-octahydro-7, 8, 8-trimethyl-4, 7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylseleno) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halogenobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p' -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, alpha-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, di (p-methoxyphenyl) phenyl methyl, di (p-N-oxido) methyl, p-halogenobenzyl, p-halobenzyl, p-nitrobenzyl, p-cyanobenzyl, p-phenoxybenzyl, p-trifluoromethylphenyl, p-phenoxybenzyl, p-nitrophenyl, p-trifluoromethylphenyl, p-nitrophenyl, p-iodobenzyl, p-iodophenyl, p-iodophenyl, p-iodophenyl, iodo, Tris (p-methoxyphenyl) methyl, 4- (4 ' -bromobenzoyloxyphenyl) diphenylmethyl, 4 ' -tris (4, 5-dichlorophthalimidophenyl) methyl, 4 ' -tris (levulinoyloxyphenyl) methyl, 4 ' -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-yl) bis (4 ', 4 ' -dimethoxyphenyl) methyl, 1-bis (4-methoxyphenyl) -1 ' -pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1, 3-benzodithiolan-2-yl, benzisothiazolyl S, s-dioxyionic group, trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), dimethylisopropylsilyl group (IPDMS), diethylisopropylsilyl group (DEIPS), dimethyl tert-hexylsilyl group, tert-butyldimethylsilyl group (TBDMS), tert-butyldiphenylsilyl group (TBDPS), tritylsilyl group, tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group (DPMS), tert-butylmethoxyphenylsilyl group (TBMPS), formate ester, benzoylformate ester, acetate ester, chloroacetate ester, dichloroacetate ester, trichloroacetate ester, trifluoroacetate ester, methoxyacetate ester, triphenylmethoxyacetate ester, phenoxyacetate ester, p-chlorophenoxyacetate ester, 3-phenylpropionate ester, 4-oxopentanoate ester (levulinate ester), 4, 4- (ethylenedithio) valerate (levulinyl dithioacetal), pivalate, adamantane ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2, 4, 6-trimethylbenzoate (mesitylate), alkyl carbonate methyl ester, 9-fluorenylmethyl carbonate (Fmoc), alkyl carbonate ethyl ester, alkyl 2, 2, 2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, allyl carbonate, alkyl p-nitrophenyl carbonate, methyl, Alkyl carbonate 3, 4-dimethoxybenzyl ester, alkyl carbonate o-nitrophenyl ester, alkyl carbonate p-nitrophenyl ester, alkyl thiocarbonate S-benzyl ester, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate, 2, 6-dichloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1, 1, 3, 3-tetramethylbutyl) phenoxyacetate, p-toluenesulfonate, iodobenzoate, 2, 6-iodomethyl-4-methylphenoxyacetate, 2, 6-chloro-4-phenoxyacetate, 2, 6-chloro-4- (1, 3, 3-tetramethylbutyl) phenoxyacetate, p-toluenesulfonate, p-phenoxyacetate, p-toluenesulfonate, p-iodobenzoate, and/p-phenoxyacetate, p-iodobenzoate, p-phenoxyacetate, p-iodobenzoate, p-phenoxyacetate, p-iodobenzoate, and/p-iodobenzoate, p-phenoxyacetate, p-iodobenzoate, p-phenoxyacetate, p-iodobenzoate, and/p-iodobenzoate, 2, 4-bis (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monobutyrate, (E) -2-methyl-2-butenoate, o- (methoxycarbonyl) benzoate, α -naphthoate, nitrate, alkyl N, N, N ', N' -tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinylsulfinyl, alkyl 2, 4-dinitrophenylsulfinate, sulfate, methanesulfonate (methanesulfonate/mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1, 2-diols or 1, 3-diols, the protective group comprises methylene acetal, ethylene acetal, 1-tert-butylethylene ketal, 1-phenylethylene ketal, (4-methoxyphenyl) ethylene acetal, 2, 2, 2-trichloroethylene acetal, acetonide, cyclopentylene ketal, cyclohexylene ketal, cycloheptylene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2, 4-dimethoxybenzylidene ketal, 3, 4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylene orthoester, 1-ethoxyethylene orthoester, 1, 2-dimethoxyethylene orthoester, 1, 3-dimethoxyethylene orthoester, α -methoxybenzylidene orthoester, 1- (N, N-dimethylamino) ethylene derivative, α - (N, N' -dimethylamino) benzylidene derivative, 2-oxacyclopentylidene orthoester, di-t-butylsilylene (DTBS), 1, 3- (1, 1, 3, 3-tetraisopropyldisiloxane) derivative (TIPDS), tetra-t-butoxydisiloxane-1, 3-diylidene derivative (TBDS), cyclic carbonate, cyclic borate, ethyl borate, and phenyl borate.

In some embodiments, the hydroxyl protecting group is acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2, 4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2, 6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4' -dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, p-tert-butyldiphenylsilyl, and mixtures thereof, Mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4 '-dimethoxytrityl (DMTr) and 4, 4' -trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2- (trimethylsilyl) ethyl (TSE), 2- (2-nitrophenyl) ethyl, 2- (4-cyanophenyl) ethyl, 2- (4-nitrophenyl) ethyl (NPE), 2- (4-nitrophenylsulfonyl) ethyl, 3, 5-dichlorophenyl, 2, 4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2, 4, 6-trimethylphenyl, 2- (2-nitrophenyl) ethyl, butylthiocarbonyl, 4, 4' -tris (benzoyloxy) trityl, diphenylcarbamoyl, acetylpropyl, 2- (dibromomethyl) benzoyl (Dbmb), 2- (isopropylthiomethoxymethyl) benzoyl (Ptmt), 9-phenylxanthen-9-yl (pixyl) or 9- (p-methoxyphenyl) xanth-9-yl (MOX). In some embodiments, each of the hydroxyl protecting groups is independently selected from acetyl, benzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 4, 4' -dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of: trityl, monomethoxytrityl and 4, 4' -dimethoxytrityl. In some embodiments, a phosphorus bond protecting group is a group that is attached to a phosphorus bond (e.g., an internucleotide bond) during the entire oligonucleotide synthesis. In some embodiments, a protecting group is attached to the sulfur atom of the phosphorothioate group. In some embodiments, the protecting group is attached to an oxygen atom of an internucleotide phosphorothioate linkage. In some embodiments, the protecting group is attached to an oxygen atom of an internucleotide phosphate linkage. In some embodiments, the protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2- (p-nitrophenyl) ethyl (NPE or Npe), 2-phenylethyl, 3- (N-tert-butylcarboxamido) -1-propyl, 4-oxopentyl, 4-methylthio-1-butyl, 2-cyano-1, 1-dimethylethyl, 4-N-methylaminobutyl, 3- (2-pyridyl) -1-propyl, 2- [ N-methyl-N- (2-pyridyl) ] aminoethyl, 2- (N-formyl, n-methyl) aminoethyl or 4- [ N-methyl-N- (2, 2, 2-trifluoroacetyl) amino ] butyl.

Subject: as used herein, the term "subject" refers to any organism to which a compound or composition is administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes, according to the present disclosure. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms, etc.) and plants. In some embodiments, the subject is a human. In some embodiments, the subject may be suffering from and/or susceptible to a disease, disorder, and/or condition.

Essentially: as used herein, the term "substantially" refers to a qualitative condition that exhibits a total or near total range or degree of a feature or characteristic of interest. One of ordinary skill in the art will appreciate that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completion or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the lack of potential completeness inherent in many biological and/or chemical phenomena.

Susceptible to: an individual "susceptible to" a disease, disorder, and/or condition is one who is at a higher risk of developing the disease, disorder, and/or condition than a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition is predisposed to the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not have been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition does not develop the disease, disorder, and/or condition.

Therapeutic agents: as used herein, the term "therapeutic agent" generally refers to any agent that, when administered to a subject, elicits a desired effect (e.g., a desired biological, clinical, or pharmaceutical effect). In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect in the appropriate population. In some embodiments, a suitable population is a population of subjects suffering from and/or susceptible to a disease, disorder, or condition. In some embodiments, the appropriate population is a population of model organisms. In some embodiments, the appropriate population may be defined by one or more criteria, such as age group, gender, genetic background, pre-existing clinical condition, prior exposure to therapy. In some embodiments, a therapeutic agent is a substance that, when administered to a subject in an effective amount, alleviates, ameliorates, inhibits, prevents, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms or features of a disease, disorder, and/or condition in the subject. In some embodiments, a "therapeutic agent" is a medicament that has been or requires approval by a governmental agency for sale to humans for administration. In some embodiments, a "therapeutic agent" is a medicament that requires a medical prescription to be administered to a human. In some embodiments, the therapeutic agent is a compound described herein.

A therapeutically effective amount of: as used herein, the term "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and/or delay the onset of a disease, disorder, and/or condition when administered to a subject suffering from or susceptible to such a disease, disorder, and/or condition. As will be appreciated by those skilled in the art, the effective amount of a substance may vary depending on factors such as the desired biological indicator, the substance to be delivered, the target cell or tissue, and the like. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and/or condition is an amount that alleviates, ameliorates, reduces, inhibits, prevents, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition. In some embodiments, the therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

Treatment: as used herein, the terms "treat", "treating" or "treating" refer to any method for partially or completely alleviating, ameliorating, alleviating, inhibiting, preventing, delaying the onset of, reducing the severity of, and/or reducing the incidence of one or more symptoms or features of a disease, disorder, and/or condition. The treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a disease, disorder, and/or condition, for example, for the purpose of reducing the risk of developing a pathology associated with the disease, disorder, and/or condition.

Unit dose: the expression "unit dose" as used herein refers to an amount administered in a single dose and/or physically discrete units of a pharmaceutical composition. In many embodiments, the unit dose contains a predetermined amount of active agent. In some embodiments, a unit dose contains an entire single dose of a pharmaceutical agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, it is necessary or expected that multiple unit doses will need to be administered in order to achieve the intended effect. A unit dose can be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined amount of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, or the like. It will be appreciated that the unit dose can be presented in a formulation that includes any of a variety of components in addition to the therapeutic agent. For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, and the like can be included, as described below. It will be appreciated by those skilled in the art that in many embodiments, the total appropriate daily dose of a particular therapeutic agent may comprise a fraction or multiple unit doses and may be determined, for example, by an attending physician within the scope of sound medical judgment. In some embodiments, a particular effective dosage level for any particular subject or organism may depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active compound used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration and the rate of excretion of the particular active compound used; the duration of treatment; drugs and/or other therapies used in combination or concomitantly with the particular compound employed; and similar factors well known in the medical arts.

Unsaturated reaction: as used herein, the term "unsaturated" means a moiety having one or more units of unsaturation.

Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structures described; for example, R and S conformations, Z and E double bond isomers, and Z and E conformational isomers for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the disclosed compounds are within the scope of the disclosure. Unless otherwise indicated, all tautomeric forms of the compounds are within the scope of the disclosure. In addition, unless otherwise indicated, structures depicted herein are also intended to encompass the presence of only one in the structureOr a plurality of isotopically enriched atoms. For example, involving replacement of hydrogen by deuterium or tritium or by¹³C or¹⁴Carbon-enriched carbon-substituted compounds having the structure of the present disclosure are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure. As will be appreciated by those skilled in the art, the provided compounds, agents, etc. may be provided in the form of solvates thereof.

3. Description of the exemplary embodiments:

in some embodiments, the present disclosure provides a medicament comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

optionally a linker moiety.

In some embodiments, the antibody binding moiety is uABT. In some embodiments, the target binding moiety may bind to CD 38. In some embodiments, the agent is a compound of formula I, I-a, I-b, II, or III, or a salt thereof. In some embodiments, the present disclosure provides a compound of formula I, I-a, I-b, II, or III, or a pharmaceutically acceptable salt thereof. Various embodiments of the provided technology are described herein as examples.

Antibody binding moieties

The present disclosure provides, inter alia, agents comprising antibody binding moieties, such as ARM. In some embodiments, the antibody binding moiety is a universal antibody binding moiety that can bind to antibodies having different Fab regions and different specificities. In some embodiments, the antibody binding portion of the present disclosure is a universal antibody binding portion that binds to an Fc region. In some embodiments, binding of the universal antibody binding moiety to the Fc region may occur simultaneously with binding of an Fc receptor (e.g., CD16a) to the same Fc region (e.g., may be at different positions/amino acid residues of the same Fc region). In some embodiments, upon binding a universal antibody binding moiety, e.g., in provided agents, compounds, methods, etc., the Fc region may still interact with the Fc receptor and perform one or more or all of its immune activities, including recruiting immune cells (e.g., effector cells, e.g., NK cells), and/or triggering, generating, promoting, and/or enhancing immune system activities, e.g., antibody-dependent cell-mediated cytotoxicity (ADCC) and/or ADCP, against a target cell, tissue, subject, and/or entity.

Various universal antibody binding moieties may be utilized in accordance with the present disclosure. Certain antibody binding moieties and techniques for identifying and/or assessing generic antibody binding moieties and/or their use in ARM are described in WO/2019/023501 and are incorporated herein by reference. Those skilled in the art will appreciate that additional techniques in the art may be suitable for identifying and/or assessing universal antibody binding moieties suitable for an ARM according to the present disclosure. In some embodiments, the universal antibody binding moiety comprises one or more amino acid residues, each of which is independently natural or non-natural. In some embodiments, the universal antibody binding moiety has

Structure (la) or a salt form thereof. In some embodiments, the universal antibody binding moiety has

Structure (la) or a salt form thereof. In some embodiments, the universal antibody binding moiety is or includes a peptide moiety, e.g., having R^c(Xaa) a moiety of the z-structure or a salt form thereof, wherein R^cEach of z and Xaa is independently as described herein. In some embodiments, one or more Xaa are independently an unnatural amino acid residue. In some embodiments, the side chains of two or more amino acid residues may be linked together to form a bridge. For example, in some embodiments, the side chains of two cysteine residues may form a disulfide bridge comprising-S- (as in many proteins, it may be formed by two-SH groups). In some embodiments, the universal antibody binding moiety is or includes a cyclic peptide moiety, e.g., having

Of the structure or its salt formsAnd (4) partial. In some embodiments, the universal antibody binding moiety is R^c- (Xaa) z-or

Or a salt form thereof, and is or includes a peptide unit. In some embodiments, - (Xaa) z-is or includes a peptide unit. In some embodiments, the peptide unit comprises an amino acid residue (e.g., at physiological pH of about 7.4, a "positively charged amino acid residue" Xaa^P) For example, residues of amino acids of the formulae A-I having positively charged side chains. In some embodiments, the peptide unit comprises R. In some embodiments, at least one Xaa is R. In some embodiments, the peptide unit is or includes an APAR. In some embodiments, the peptide unit is or comprises RAPA. In some embodiments, the peptide unit comprises an amino acid residue, e.g., a residue of an amino acid of formula a-I having a side chain comprising an aromatic group ("aromatic amino acid residue" Xaa)^A). In some embodiments, the peptide unit includes a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit comprises W. In some embodiments, the peptide unit includes a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit is or comprises Xaa^AXaaXaa^PXaa^P. In some embodiments, the peptide unit is or comprises Xaa ^PXaa^PXaaXaa^A. In some embodiments, the peptide unit is or comprises Xaa^PXaa^AXaa^P. In some embodiments, the peptide unit is or comprises two or more Xaa^PXaa^AXaa^P. In some embodiments, the peptide unit is or comprises Xaa^PXaa^AXaa^PXaaXaa^PXaa^AXaa^P. In some embodiments, the peptide unit is or comprises Xaa^PXaa^PXaa^AXaa^AXaa^P. In some embodiments, the peptide unit is or comprises Xaa^PXaa^PXaa^PXaa^A. In some embodiments, the peptide unit is or comprises two or more Xaa^AXaa^AXaa^P. In some embodiments, the peptide residue comprises one or more prolinesAn acid residue. In some embodiments, the peptide unit is or comprises HWRGWA. In some embodiments, the peptide unit is or comprises WGRR. In some embodiments, the peptide unit is or comprises RRGW. In some embodiments, the peptide unit is or comprises NKFRGKYK. In some embodiments, the peptide unit is or comprises NRFRGKYK. In some embodiments, the peptide unit is or comprises NARKFYK. In some embodiments, the peptide unit is or comprises NARKFYKG. In some embodiments, the peptide unit is or comprises HWRGWV. In some embodiments, the peptide unit is or comprises KHFRNKD. In some embodiments, a peptide unit includes positively charged amino acid residues, aromatic amino acid residues, and amino acid residues, such as the residues of amino acids of formulae a-I having a negatively charged side chain (e.g., at physiological pH of about 7.4, "negatively charged amino acid residue" Xaa) ^N). In some embodiments, the peptide residue is RHRFNKD. In some embodiments, the peptide unit is TY. In some embodiments, the peptide unit is TYK. In some embodiments, the peptide unit is RTY. In some embodiments, the peptide unit is RTYK. In some embodiments, the peptide unit is or comprises a sequence selected from PAM. In some embodiments, the peptide unit is WHL. In some embodiments, the peptide unit is ELVW. In some embodiments, the peptide unit is or includes a sequence selected from AWHLGELVW. In some embodiments, the peptide unit is or includes a sequence selected from DCAWHLGELVWCT in which two cysteine residues may form a disulfide bond, as seen in native proteins. In some embodiments, the peptide unit is or includes a sequence selected from Fc-III. In some embodiments, the peptide unit is or includes a sequence selected from DpLpAWHLGELVW. In some embodiments, the peptide unit is or includes a sequence selected from FcBP-1. In some embodiments, the peptide unit is or comprises a sequence selected from dplpdcahlglcvwct. In some embodiments, the peptide unit is or includes a sequence selected from FcBP-2. In some embodiments, the peptide unit is or includes a sequence selected from CDCAWHLGELVWCTC, wherein the first and last cysteines and the two cysteines in the middle of the sequence may each independently form a disulfide bond as in the native protein. In some embodiments, the peptide unit is or includes a sequence selected from Fc-III-4 c. In some embodiments, the peptide unit is or comprises an FcRM selected from And (4) sequencing. In some embodiments, the peptide unit is or comprises a cyclic peptide unit. In some embodiments, the cyclic peptide unit includes an amide group formed by an amino group of the side chain and the C-terminal-COOH.

In some embodiments, - (Xaa) z-is or includes [ X¹]_p1[X²]_p2-X³X⁴X⁵X⁶X⁷X⁸X⁹X¹⁰X¹¹X¹²-[X¹³]_p13-[X¹⁴]_p14[X¹⁵]_p15[X¹⁶]_p16Wherein X is¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹、X¹²And X¹³Each of which is independently an amino acid residue, e.g., an amino acid of formula a-I, and each of p1, p2, p13, p14, p15, and p16 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, X¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹、X¹²And X¹³Each of which is independently an amino acid residue of an amino acid of formula a-I. In some embodiments, X¹、X²、X³、X⁴、X⁴、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹、X¹²And X¹³Each of which is independently a natural amino acid residue. In some embodiments, X¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹、X¹²And X¹³Is an unnatural amino acid residue as described in the disclosure.

In some embodiments, the peptide unit includes a functional group of an amino acid residue that is reactive with a functional group of another amino acid residue. In some embodiments, the peptide unit comprises a peptide havingAn amino acid residue of a side chain comprising a functional group that can react with another functional group of a side chain of another amino acid residue to form a bond (see, e.g., the moieties described in table a-1, table 1, etc.). In some embodiments, one functional group of one amino acid residue is linked to a functional group of another amino acid residue to form a bond (or bridge). The bond is to the backbone atom of the peptide unit and does not include the backbone atom. In some embodiments, a peptide unit comprises a bond formed by two side chains of non-adjacent amino acid residues. In some embodiments, the bond is bonded to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, both backbone atoms bonded to the bond are carbon atoms. In some embodiments, the key has L ^bStructure of, wherein L^bIs L as described in this disclosure^aWherein L is^aNot a covalent bond. In some embodiments, L^aincluding-Cy-. In some embodiments, L^aincluding-Cy-wherein-Cy-is optionally substituted heteroaryl. In some embodiments, -Cy-is

In some embodiments, L^aIs composed of

In some embodiments, such L^aCan be derived from the side chain of an amino acid residue₃Formation of a group and a side chain of another amino acid residue. In some embodiments, the bond is formed via the attachment of two thiol groups, e.g., two cysteine residues. In some embodiments, L^aincluding-S-S-. In some embodiments, L^ais-CH₂-S-S-CH₂-. In some embodiments, the bond is via an amino group (e.g., -NH in the side chain of a lysine residue)₂) And a carboxylic acid group (e.g., -COOH in the side chain of an aspartic acid or glutamic acid residue). In some embodiments, L^acomprising-C (O) -N (R') -. In some embodiments, L^aincluding-C (O) -NH-. In some embodiments, L^ais-CH₂CONH-(CH₂)₃-。In some embodiments, L^aincluding-C (O) -N (R ') -, where R' is R, and forms a ring with the R group on the peptide backbone (e.g., as in A-34). In some embodiments, L^aIs- (CH)₂)₂-N(R′)-CO--(CH₂)₂-. In some embodiments, -Cy-is optionally substituted phenylene. In some embodiments, -Cy-is optionally substituted 1, 2-phenylene. In some embodiments, L ^aIs composed of

In some embodiments, L^aIs composed of

In some embodiments, L^aIs optionally substituted divalent C_2-20A divalent aliphatic group. In some embodiments, L^aIs optionally substituted- (CH)₂)₉-CH＝CH-(CH₂)₉-. In some embodiments, L^aIs- (CH)₂)₃-CH＝CH-(CH₂)₃-。

In some embodiments, the two amino acid residues bonded to the bond are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more than 15 amino acid residues (not including the two amino acid residues bonded to the bond). In some embodiments, the number is 1. In some embodiments, the number is 2. In some embodiments, the number is 3. In some embodiments, the number is 4. In some embodiments, the number is 5. In some embodiments, the number is 6. In some embodiments, the number is 7. In some embodiments, the number is 8. In some embodiments, the number is 9. In some embodiments, the number is 10. In some embodiments, the number is 11. In some embodiments, the number is 12. In some embodiments, the number is 13. In some embodiments, the number is 14. In some embodiments, the number is 15.

In some embodiments, each of p1, p2, p13, p14, p15, and p16 is 0. In some embodiments, - (Xaa) z-is or includes-X ³X⁴X⁵X⁶X⁷X⁸X⁹X¹⁰X¹¹X¹²-, wherein:

X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹and X¹²Each of which is independently an amino acid residue;

X⁶is Xaa^AOr Xaa^P；

X⁹Is Xaa^N(ii) a And is

X¹²Is Xaa^AOr Xaa^P。

In some embodiments, X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹And X¹²Each of which is independently an amino acid residue of an amino acid of formula a-I as described in the present disclosure. In some embodiments, X⁵Is Xaa^AOr Xaa^P. In some embodiments, X⁵Is Xaa^A. In some embodiments, X⁵Is Xaa^P. In some embodiments, X⁵Is an amino acid residue whose side chain includes an optionally substituted saturated, partially saturated or aromatic ring. In some embodiments, X⁵Is composed of

In some embodiments, X⁵Is composed of

In some embodiments, X⁶Is Xaa^A. In some embodiments, X⁶Is Xaa^P. In some embodiments, X⁶Is His. In some embodiments, X¹²Is Xaa^A. In some embodiments, X¹²Is Xaa^P. In some embodiments, X⁹Is Asp. In some embodiments, X⁹Is Glu. In some embodiments, X¹²Is composed of

In some embodiments, X¹²Is composed of

In some embodiments, X⁷、X¹⁰And X¹¹Each of which is independently an amino acid residue having a hydrophobic side chain (a "hydrophobic amino acid residue" Xaa)^H). In some embodiments, X⁷Is Xaa^H. In some embodiments, X ⁷Is composed of

In some embodiments, X⁷Is Val. In some embodiments, X¹⁰Is Xaa^H. In some embodiments, X¹⁰Is Met. In some embodiments, X¹⁰Is composed of

In some embodiments, X¹¹Is Xaa^H. In some embodiments, X¹¹Is composed of

In some embodiments, X⁸Is Gly. In some embodiments, X⁴Is Pro. In some embodiments, X³Is Lys. In some embodiments, X¹²of-COOH with Lys (X)³) The side chain amino group of (A) forms an amide bond, and Lys (X)³) Is linked to a linker moiety and then to a target binding moiety.

In some embodiments, - (Xaa) z-is or includes-X³X⁴X⁵X⁶X⁷X⁸X⁹X¹⁰X¹¹X¹²-, wherein:

X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹and X¹²Each of which is independently an amino acid residueA group;

at least two amino acid residues via one or more bonds L^bConnecting;

L^bis selected from C₁-C₂₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₂₀A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution wherein L is^b(ii) is bonded to, and does not include, a backbone atom of one amino acid residue and a backbone atom of another amino acid residue;

X⁶is Xaa^AOr Xaa^P；

X⁹Is Xaa^N(ii) a And is

X¹²Is Xaa^AOr Xaa^P。

In some embodiments, X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹And X¹²Each of which is independently an amino acid residue of an amino acid of formula a-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are through L^bAnd (4) connecting. In some embodiments, X⁵And X¹⁰Through L^bAnd (4) connecting. In some embodiments, there is one key L^b. In some embodiments, X⁶Is Xaa^A. In some embodiments, X⁶Is Xaa^P. In some embodiments, X⁶Is His. In some embodiments, X⁹Is Asp. In some embodiments, X⁹Is Glu. In some embodiments, X¹²Is Xaa^A. In some embodiments, X¹²Is composed of

In some embodiments of the present invention, the,X¹²is composed of

In some embodiments, X¹²Is composed of

In some embodiments, X⁴、X⁷And X¹¹Each of which is independently Xaa^H. In some embodiments, X⁴Is Xaa^H. In some embodiments, X⁴Is Ala. In some embodiments, X⁷Is Xaa^H. In some embodiments, X⁷Is composed of

In some embodiments, X¹¹Is Xaa^H. In some embodiments, X¹¹Is composed of

In some embodiments, X⁸Is Gly. In some embodiments, X³Is Lys. In some embodiments, X¹²of-COOH with Lys (X)³) The side chain amino group of (A) forms an amide bond, and Lys (X)³) Is linked to a linker moiety and then to a target binding moiety. In some embodiments, L ^bIs composed of

In some embodiments, L^bIs composed of

In some embodiments, L^bTwo alpha-carbon atoms connecting two different amino acid residues. In some embodiments, X⁵And X¹⁰Are both Cys, and the two-SH groups of their side chains form-S-S- (L)^bis-CH₂-S-S-CH₂-)。

In some embodiments, - (Xaa) z-is or includes-X²X³X⁴X⁵X⁶X⁷X⁸X⁹X¹⁰X¹¹X¹²-, wherein:

X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹and X¹²Each of which is independently an amino acid residue;

at least two amino acid residues via one or more bonds L^bConnecting;

X⁴is Xaa^A；

X⁵Is Xaa^AOr Xaa^P；

X⁸Is Xaa^N(ii) a And is

X¹¹Is Xaa^A。

In some embodiments, X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹And X¹²Each of which is independently an amino acid residue of an amino acid of formula a-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are through L^bAnd (4) connecting. In some embodiments, there is one key L^b. In some embodiments, X ²And X¹²Through L^bAnd (4) connecting. In some embodiments, L^bis-CH₂-S-S-CH₂-. In some embodimentsIn, L^bis-CH₂-CH₂-S-CH₂-. In some embodiments, L^bIs composed of

In some embodiments, L^bIs composed of

In some embodiments, L^bis-CH₂CH₂CO-N(R′)-CH₂CH₂-. In some embodiments, R 'and-N (R') -CH₂CH₂The R groups on the backbone atoms to which they are bonded together form a ring, for example as in A-34. In some embodiments, the formed ring is 3-, 4-, 5-, 6-, 7-, or 8-membered. In some embodiments, the ring formed is monocyclic. In some embodiments, the formed ring is saturated. In some embodiments, L^bIs composed of

In some embodiments, L^bTwo alpha-carbon atoms connecting two different amino acid residues. In some embodiments, X⁴Is Xaa^A. In some embodiments, X⁴Is Tyr. In some embodiments, X⁵Is Xaa^A. In some embodiments, X⁵Is Xaa^P. In some embodiments, X⁵Is His. In some embodiments, X⁸Is Asp. In some embodiments, X⁸Is Glu. X¹¹Is Tyr. In some embodiments, X²And X¹²Are both Cys, and the two-SH groups of their side chains form-S-S- (L)^bis-CH₂-S-S-CH₂-). In some embodiments, X³、X⁶、X⁹And X¹⁰Each of which is independently Xaa ^H. In some embodiments, X³Is Xaa^H. In some embodiments, X³Is Ala. In some embodiments, X⁶Is Xaa^H. In some embodiments, X⁶Is Leu. In some embodiments, X⁹Is Xaa^H. In some embodiments, X⁹Is Leu. In some embodiments, X⁹Is composed of

In some embodiments, X¹⁰Is Xaa^H. In some embodiments, X¹⁰Is Val. In some embodiments, X¹⁰Is composed of

In some embodiments, X⁷Is Gly. In some embodiments, p1 is 1. In some embodiments, X¹Is Asp. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X¹³Is an amino acid residue comprising a polar uncharged side chain (e.g., at physiological pH, "polar uncharged amino acid residue" Xaa^L). In some embodiments, X¹³Is Thr. In some embodiments, X¹³Is Val. In some embodiments, p13 is 0. In some embodiments, R^cis-NHCH₂CH(OH)CH₃. In some embodiments, R^cIs (R) -NHCH₂CH(OH)CH₃. In some embodiments, R^cIs (S) -NHCH₂CH(OH)CH₃。

at least two amino acid residues via one or more bonds L ^bConnecting;

L^bis selected from C₁-C₂₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₂₀Heteroaliphatic groupOptionally substituted divalent radical of (a) wherein one or more methylene units of said radical are optionally and independently substituted by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution wherein L is^b(ii) is bonded to, and does not include, a backbone atom of one amino acid residue and a backbone atom of another amino acid residue;

X⁵is Xaa^AOr Xaa^P；

X⁸Is Xaa^N(ii) a And is

X¹¹Is Xaa^A。

In some embodiments, X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹And X¹²Each of which is independently an amino acid residue of an amino acid of formula a-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are through L^bAnd (4) connecting. In some embodiments, there is one key L^b. In some embodiments, there are two or more bonds L^b. In some embodiments, there are two keys L^b. In some embodiments, X²And X¹²Through L^bAnd (4) connecting. In some embodiments, X⁴And X⁹Through L^bAnd (4) connecting. In some embodiments, X⁴And X¹⁰Through L^bAnd (4) connecting. In some embodiments, L^bis-CH₂-S-S-CH₂-. In some embodiments, L^bIs composed of

In some embodiments, L^bIs composed of

In some embodiments, X²And X¹²Both Cys and two of their side chains with-SH groups forming-S- (L)^bis-CH₂-S-S-CH₂-). In some embodiments, X⁴And X¹⁰Are both Cys, and the two-SH groups of their side chains form-S-S- (L)^bis-CH₂-S-S-CH₂-). In some embodiments, X⁴And X⁹Through L^bIs connected, wherein L^bIs composed of

In some embodiments, X⁴And X⁹Through L^bIs connected, wherein L^bIs composed of

In some embodiments, X⁵Is Xaa^A. In some embodiments, X⁵Is Xaa^P. In some embodiments, X⁵Is His. In some embodiments, X⁸Is Asp. In some embodiments, X⁸Is Glu. In some embodiments, X¹¹Is Tyr. In some embodiments, X¹¹Is composed of

In some embodiments, X²And X¹²Through L^bIs connected, wherein L^bis-CH₂-S-CH₂CH₂-. In some embodiments, L^bTwo alpha-carbon atoms connecting two different amino acid residues. In some embodiments, X³、X⁶And X⁹Each of which is independently Xaa^H. In some embodiments, X³Is Xaa^H. In some embodiments, X³Is Ala. In some embodiments, X⁶Is Xaa^H. In some embodiments, X⁶Is Leu. In some embodiments, X⁶Is composed of

In some embodiments, X⁹Is Xaa^H. In some embodiments, X⁹Is Leu. In some casesIn the examples, X⁹Is composed of

In some embodiments, X¹⁰Is Xaa^H. In some embodiments, X ¹⁰Is Val. In some embodiments, X⁷Is Gly. In some embodiments, p1 is 1. In some embodiments, X¹Is Xaa^N. In some embodiments, X¹Is Asp. In some embodiments, X¹Is Glu. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X¹³Is Xaa^L. In some embodiments, X¹³Is Thr. In some embodiments, X¹³Is Val.

In some embodiments, - (Xaa) z-is or includes-X²X³X⁴X⁵X⁶X⁷X⁸X⁹X¹⁰X¹¹X¹²X¹³X¹⁴X¹⁵X¹⁶-, wherein:

X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹、X¹²、X¹³、X¹⁴、X¹⁵and X¹⁶Each of which is independently an amino acid residue;

at least two amino acid residues via a bond L^bConnecting;

L^bis selected from C₁-C₂₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₂₀A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution wherein L is^bBound to the main chain atom of one amino acid residue and to the main chain atom of another amino acid residueChain atoms, and not including backbone atoms;

X³is Xaa^N；

X⁶Is Xaa^A；

X⁷Is Xaa^AOr Xaa^P；

X⁹Is Xaa^N(ii) a And is

X¹³Is Xaa^A。

In some embodiments, X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹And X¹²Each of which is independently an amino acid residue of an amino acid of formula a-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are through L ^bAnd (4) connecting. In some embodiments, there is one key L^b. In some embodiments, there are two or more bonds L^b. In some embodiments, there are two keys L^b. In some embodiments, X²Through L^bIs connected to X¹⁶. In some embodiments, X⁴Through L^bIs connected to X¹⁴. In some embodiments, X²And X¹⁶Are both Cys, and the two-SH groups of their side chains form-S-S- (L)^bis-CH₂-S-S-CH₂-). In some embodiments, X⁴And X¹⁴Are both Cys, and the two-SH groups of their side chains form-S-S- (L)^bis-CH₂-S-S-CH₂-). In some embodiments, L^bTwo alpha-carbon atoms connecting two different amino acid residues. In some embodiments, X³Is Asp. In some embodiments, X³Is Glu. In some embodiments, X⁵Is Xaa^H. In some embodiments, X⁵Is Ala. In some embodiments, X⁶Is Xaa^A. In some embodiments, X⁶Is Tyr. In some embodiments, X⁷Is Xaa^A. In some embodiments, X⁷Is Xaa^P. In some embodiments, X⁷Is His. At one endIn some embodiments, X⁸Is Xaa^H. In some embodiments, X⁸Is Ala. In some embodiments, X⁹Is Gly. In some embodiments, X¹⁰Is Asp. In some embodiments, X¹⁰Is Glu. In some embodiments, X ¹¹Is Xaa^H. In some embodiments, X¹¹Is Leu. In some embodiments, X¹²Is Xaa^H. In some embodiments, X¹²Is Val. In some embodiments, X¹³Is Xaa^A. In some embodiments, X¹³Is Tyr. In some embodiments, X¹⁵Is Xaa^L. In some embodiments, X¹⁵Is Thr. In some embodiments, X¹⁵Is Val. In some embodiments, p1 is 1. In some embodiments, X¹Is Xaa^N. In some embodiments, X¹Is Asp. In some embodiments, X¹Is Glu.

As will be appreciated by those skilled in the art, an amino acid residue may be replaced by another amino acid residue having similar properties, e.g., Xaa^H(e.g., Val, Leu, etc.) may be substituted with another Xaa^H(e.g., Leu, Ile, Ala, etc.) substitution, a Xaa^ACan be substituted by another Xaa^AReplacement, one Xaa^PCan be substituted by another Xaa^PReplacement, one Xaa^NCan be substituted by another Xaa^NReplacement, one Xaa^LCan be substituted by another Xaa^LPermutation, and the like.

In some embodiments, the antibody binding moiety (e.g., a universal antibody binding moiety) is or includes an optionally substituted moiety of table a-1 in some embodiments, the antibody binding moiety (e.g., a universal antibody binding moiety) is selected from table a-1.

TABLE A-1 exemplary antibody binding moieties.

In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-1. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-2. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-3. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-4. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-5. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-6. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-7. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-8. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-9. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-10. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-11. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-12. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-13. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-14. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-15. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-16. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-17. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-18. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-19. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-20. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-21. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-22. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-23. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-24. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-25. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-26. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-27. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-28. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-29. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-30. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-31. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-32. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-33. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-34. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-35. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-36. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-37. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-38. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-39. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-40. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-41. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-42. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-43. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-44. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-45. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-46. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-47. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-48. In some embodiments, the universal antibody binding moiety is or includes optionally substituted a-49.

In some embodiments, the universal antibody binding moiety is A-1. In some embodiments, the universal antibody binding moiety is a-2. In some embodiments, the universal antibody binding moiety is a-3. In some embodiments, the universal antibody binding moiety is a-4. In some embodiments, the universal antibody binding moiety is a-5. In some embodiments, the universal antibody binding moiety is a-6. In some embodiments, the universal antibody binding moiety is a-7. In some embodiments, the universal antibody binding moiety is a-8. In some embodiments, the universal antibody binding moiety is a-9. In some embodiments, the universal antibody binding moiety is A-10. In some embodiments, the universal antibody binding moiety is a-11. In some embodiments, the universal antibody binding moiety is a-12. In some embodiments, the universal antibody binding moiety is a-13. In some embodiments, the universal antibody binding moiety is A-14. In some embodiments, the universal antibody binding moiety is a-15. In some embodiments, the universal antibody binding moiety is a-16. In some embodiments, the universal antibody binding moiety is a-17. In some embodiments, the universal antibody binding moiety is A-18. In some embodiments, the universal antibody binding moiety is a-19. In some embodiments, the universal antibody binding moiety is A-20. In some embodiments, the universal antibody binding moiety is a-21. In some embodiments, the universal antibody binding moiety is a-22. In some embodiments, the universal antibody binding moiety is a-23. In some embodiments, the universal antibody binding moiety is A-24. In some embodiments, the universal antibody binding moiety is a-25. In some embodiments, the universal antibody binding moiety is a-26. In some embodiments, the universal antibody binding moiety is a-27. In some embodiments, the universal antibody binding moiety is a-28. In some embodiments, the universal antibody binding moiety is a-29. In some embodiments, the universal antibody binding moiety is A-30. In some embodiments, the universal antibody binding moiety is a-31. In some embodiments, the universal antibody binding moiety is a-32. In some embodiments, the universal antibody binding moiety is a-33. In some embodiments, the universal antibody binding moiety is a-34. In some embodiments, the universal antibody binding moiety is a-35. In some embodiments, the universal antibody binding moiety is A-36. In some embodiments, the universal antibody binding moiety is a-37. In some embodiments, the universal antibody binding moiety is a-38. In some embodiments, the universal antibody binding moiety is a-39. In some embodiments, the universal antibody binding moiety is A-40. In some embodiments, the universal antibody binding moiety is A-41. In some embodiments, the universal antibody binding moiety is A-42. In some embodiments, the universal antibody binding moiety is a-43. In some embodiments, the universal antibody binding moiety is a-44. In some embodiments, the universal antibody binding moiety is a-45. In some embodiments, the universal antibody binding moiety is A-46. In some embodiments, the universal antibody binding moiety is a-47. In some embodiments, the universal antibody binding moiety is a-48. In some embodiments, the universal antibody binding moiety is a-49.

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the antibody binding moiety is or comprises

In some embodiments, the universal antibody binding moiety comprises a peptide unit and is linked to the linker moiety via the C-terminus of the peptide unit. In some embodiments, it is linked to the linker moiety via the N-terminus of the peptide unit. In some embodiments, it is linked to the linker via a side chain group of the peptide unit. In some embodiments, the universal antibody binding moiety comprises a peptide unit and is linked to the target binding moiety via the C-terminus of the peptide unit, optionally via a linker moiety. In some embodiments, the universal antibody binding moiety comprises a peptide unit and is linked to the target binding moiety via the N-terminus of the peptide unit, optionally via a linker moiety. In some embodiments, the universal antibody binding moiety comprises a peptide unit and is linked to the target binding moiety via a side chain of the peptide unit, optionally via a linker moiety.

In some embodiments, an antibody binding moiety (e.g., a universal antibody binding moiety) is or includes a small molecule entity with a molecular weight of, for example, less than 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, and the like. Suitable such antibody binding moieties comprise small molecule Fc binding agent moieties such as those described in US 9,745,339, US 201/30131321 and the like. In some embodiments, the antibody binding moiety has a structure whose corresponding compound is a compound described in US 9,745,339 or US 2013/0131321, the compounds of each of which are independently incorporated herein by reference. In some embodiments, ABT has the structure of H-ABT is a compound described in US 9,745,339 or US 2013/0131321, the compounds of each of which are independently incorporated herein by reference. In some embodiments, such compounds can bind to antibodies. In some embodiments, such compounds can bind to the Fc region of an antibody.

In some embodiments, the antibody binding moiety, e.g., ABT, is or includes optionally substituted

In some embodiments, ABT is or comprises

In some embodiments, ABT is or includes optionally substituted

In some embodiments, ABT is or comprises

In some embodiments, ABT is or includes optionally substituted

In some embodiments, ABT is or comprises

In some embodiments, ABT is or includes optionally substituted

In some embodiments, ABT is or comprises

In some embodiments, the antibody binding moiety is a triazine moiety, such as the triazine moiety described in US 2009/0286693. In some embodiments, the antibody binding portion has a structure whose corresponding compound is that described in US 2009/0286693, which compounds are independently incorporated herein by reference. In some embodiments, ABT has the structure of H-ABT is a compound described in US 2009/0286693, which compounds are independently incorporated herein by reference. In some embodiments, such compounds can bind to antibodies. In some embodiments, such compounds can bind to the Fc region of an antibody.

In some embodiments, the antibody binding moiety is a triazine moiety, such as Teng et al, a strategy to generate biomimetic ligands for affinity chromatography (a strategy for the generation of biological ligands for affinity chromatography), Combinatorial synthesis and biological evaluation of IgG binding ligands (Combinatorial synthesis and biological evaluation of an IgG binding ligand), journal of molecular recognition (j.mol.recognition.) 1999; 12: 67-75 ("Teng"). In some embodiments, the antibody-binding portion has a structure whose corresponding compound is that described in Teng, which compounds are independently incorporated herein by reference. In some embodiments, ABT has the structure of H-ABT being a compound described in Teng, which compounds are independently incorporated herein by reference. In some embodiments, such compounds can bind to antibodies. In some embodiments, such compounds can bind to the Fc region of an antibody.

In some embodiments, the antibody binding moiety is a Triazine moiety, such as Uttamchandri et al, a microarray combining a Triazine library for labeling in Small Molecule ligand Discovery of Human IgG (microarray of labeled Combinatorial ligand conjugates in the Discovery of Small-Molecule Ligands of Human IgG), journal of Combinatorial chemistry (J Comb Chem.) 2004 from month 11 to month 12; 6(6): 862-8 ("Uttamchandri"). In some embodiments, the antibody-binding portion has a structure whose corresponding compound is that described in ottamchandani, which compounds are independently incorporated herein by reference. In some embodiments, the ABT has the structure where H-ABT is a compound described in ottamchandani, which compounds are independently incorporated herein by reference. In some embodiments, such compounds can bind to antibodies. In some embodiments, such compounds can bind to the Fc region of an antibody.

In some embodiments, the antibody binding moiety binds to one or more binding sites of protein a. In some embodiments, the antibody binding moiety binds to one or more binding sites of protein G. In some embodiments, the antibody binding moiety binds to one or more binding sites of protein L. In some embodiments, the antibody binding moiety binds to one or more binding sites of protein Z. In some embodiments, the antibody binding moiety binds to one or more binding sites of the protein LG. In some embodiments, the antibody binding moiety binds to one or more binding sites of the protein LA. In some embodiments, the antibody binding moiety binds to one or more binding sites of the protein AG. In some embodiments, the antibody binding moiety is described in Choe, w., Durgannavar, t.a., and Chung, S.J. (2016.) Fc binding ligands of immunoglobulin G: an overview of high affinity proteins and peptides (Fc-binding ligands of immunoglobulin G: An overview of high affinity proteins and peptides) Materials (Materials), 9(12) https:// doi.org/10.3390/ma 9120994.

In some embodiments, the antibody binding moiety can bind to a nucleotide binding site. In some embodiments, the antibody binding moiety is a small molecule moiety that can bind to a nucleotide binding site. In some embodiments, the small molecule is a tryptamine. In some embodiments, the ABT has a structure where H-ABT is tryptamine. Some suitable techniques are described in Mustafaoglu et al, using Affinity Membrane Chromatography methods using Small Molecule targeted Nucleotide Binding sites for antibody Purification (Purification via Affinity Membrane Chromatography Method) with analysts (analysts) 2016, 11/28 days; 141(24): 6571 and 6582.

A number of techniques are available for identifying and/or assessing and/or characterizing antibody binding moieties, including generic antibody binding moieties, and/or their use in ARM, for example the techniques described in WO/2019/023501, the techniques of which are incorporated herein by reference. In some embodiments, the antibody-binding moiety is a moiety (e.g., a small molecule moiety, a peptide moiety, a nucleic acid moiety, etc.) that can selectively bind to IgG and can provide and/or stimulate ADCC and/or ADCP when used in ARM. In some embodiments, the antibody-binding portion can be identified using peptide display techniques (e.g., phase display, non-cell display, etc.). In some embodiments, an antibody-binding moiety is a moiety (e.g., a small molecule moiety, a peptide moiety, a nucleic acid moiety, etc.) that can bind to IgG and optionally can compete with known antibody-binding agents (e.g., protein a, protein G, protein L, etc.).

As will be appreciated by those of skill in the art, antibodies having various properties and activities (e.g., antibodies recognizing different antigens, having optional modifications, etc.) can be recruited through the antibody binding portions described in the present disclosure. In some embodiments, such antibodies comprise an antibody administered to a subject, e.g., for therapeutic purposes. In some embodiments, the antibody recruited by the antibody binding portion comprises an antibody directed against a different antigen. In some embodiments, the antibody recruited by the antibody binding portion comprises an antibody for which the antigen is not present on the surface or cell membrane of a target cell (e.g., a target cell such as a cancer cell). In some embodiments, the antibody recruited by the antibody binding moiety comprises an antibody that does not target an antigen present on the surface or cell membrane of a target (e.g., a target cell, such as a cancer cell). In some embodiments, antigens on the surface of a target cell may interfere with the structure, conformation, and/or one or more properties and/or activities of a recruited antibody that binds such antigen. In some embodiments, as will be appreciated by those of skill in the art, the provided techniques include recruiting a universal antibody binding portion of antibodies with diverse specificities, and no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the recruited antibodies are directed to the same antigen, protein, lipid, carbohydrate, etc. Furthermore, it is an advantage of the present disclosure that the provided technology comprising a universal antibody binding moiety can utilize a diverse pool of antibodies, such as the pool of antibodies present in serum. In some embodiments, a universal antibody binding moiety of the present disclosure (e.g., a universal antibody binding moiety in ARM) is contacted with a plurality of antibodies, wherein no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the plurality of antibodies are directed against the same antigen, protein, lipid, carbohydrate, etc.

CD38

CD38 (differentiation group 38, also known as cyclic ADP ribohydrolases) is expressed by different types of cells and performs multiple functions. It has been reported that in many immune cells, for example CD4⁺、CD8⁺CD38 was found on the surface of B lymphocytes and natural killer cells as a glycoprotein. Other functions of CD38, such as cell adhesion, signaling, and calcium signaling, have also been reported. In various embodimentsIn (3), CD38 is human CD 38.

In some embodiments, CD38 is reported to be a non-lineage-restricted type II transmembrane glycoprotein that synthesizes and hydrolyzes cyclic adenosine 5' -diphosphate-ribose (intracellular calcium ion mobilization messenger). It is reported that the release of soluble proteins and the ability of membrane-bound proteins to be internalized may be indicative of both extracellular and intracellular functions of the protein. According to certain reports, CD38 has, in each case, an N-terminal cytoplasmic tail, a single transmembrane domain, and a C-terminal extracellular region with four N-glycosylation sites. Analysis of the crystal structure reportedly indicates that the functional molecule is a dimer, in which the central portion contains the catalytic site. CD38 has been reported to be useful as a prognostic marker for patients with chronic lymphocytic leukemia. Alternative splicing has been reported and can result in a variety of transcriptional variants.

CD38 has been reported to be expressed on immune system cells (e.g., T cells or B cells) of healthy individuals. In some embodiments, in certain conditions, disorders or diseases, an increase in CD38 expression and/or activity levels is observed in cells that do not normally have or have lower levels of CD 38.

CD38 is associated with various conditions, disorders or diseases, such as HIV infection and various cancers, such as leukemia, myeloma, solid tumors, Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM), Acute Promyelocytic Leukemia (APL), non-Hodgkin's lymphoma, B-and T-cell acute lymphocytic leukemia, acute myelogenous leukemia, Hodgkin's lymphoma, chronic myelogenous leukemia, and the like.

Daratumab (an antibody targeting CD 38) has been approved for the treatment of multiple myeloma.

Target binding moieties

Various types and chemical classes of target-binding moieties can be utilized in accordance with the present disclosure. In addition, the compounds of the present disclosure include a target binding moiety that can bind to CD 38. In some embodiments, the target binding moiety binds to a characteristic agent, such as CD 38. In some embodiments, the target binding moiety is or includes a peptide moiety. In some embodiments, the target binding moiety is or includes a nucleic acid agent, such as an aptamer. In some embodiments, the target binding moiety is or comprises a lipid moiety. Certain types of target-binding moieties are described below; those skilled in the art will appreciate that other types of target-binding moieties, including many known in the art, may also be utilized in accordance with the present disclosure. As will be appreciated by those skilled in the art, various techniques are readily available and may be used to assess and confirm CD38 binding. Certain useful techniques are described in the examples.

a. Small molecules

In some embodiments, the target binding moiety is a small molecule moiety. In some embodiments, the small molecule moiety has a molecular weight of no more than 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, 900, 800, 700, or 600. In some embodiments, the small molecule moiety has a molecular weight of no more than 8000. In some embodiments, the small molecule moiety has a molecular weight of no more than 7000. In some embodiments, the small molecule moiety has a molecular weight of no more than 6000. In some embodiments, the small molecule moiety has a molecular weight of no more than 5000. In some embodiments, the small molecule moiety has a molecular weight of no more than 4000. In some embodiments, the small molecule moiety has a molecular weight of no more than 3000. In some embodiments, the small molecule moiety has a molecular weight of no more than 2000. In some embodiments, the small molecule moiety has a molecular weight of no more than 1500. In some embodiments, the small molecule moiety has a molecular weight of no more than 1000. In some embodiments, the small molecule moiety has a molecular weight of no more than 900. Further, the present disclosure encompasses the following recognition: the small molecule target-binding moiety may be capable of binding to a marker, such as CD38, external, on the surface, and/or internal to the target (e.g., cancer cells).

In some embodiments, the small molecule target binding moiety is or includes a moiety that selectively binds to a protein or fragment thereof (e.g., CD 38).

b. Peptide agents

In some embodiments, the target binding moiety is or includes a peptide agent. In some embodiments, the target binding moiety is a peptide moiety. In some embodiments, the peptide moiety can be linear or cyclic. In some embodiments, the target binding moiety is or includes a cyclic peptide moiety. Various peptide target binding moieties are known in the art and can be utilized in accordance with the present disclosure.

In some embodiments, the target binding moiety is or comprises a peptide aptamer agent.

c. Aptamer agents

In some embodiments, the target binding moiety is or comprises a nucleic acid agent. In some embodiments, the target binding moiety is or comprises an oligonucleotide moiety. In some embodiments, the target binding moiety is or comprises an aptamer agent. Various aptamer agents are known in the art or can be readily developed using common techniques, and can be used in the techniques provided in accordance with the present disclosure.

In some embodiments, a target binding moiety, for example, one that can bind to CD38, is or includes a peptide moiety. In some embodiments, the peptide moiety is or includes (Xaa) y or a salt form thereof as described herein. In some embodiments, a target binding moiety, e.g., one that can bind to CD38, is or includes a peptide moiety, e.g., a moiety having the structure:

Or a salt thereof, wherein:

each Xaa is independently a residue of an amino acid or amino acid analog;

y is 5 to 20;

L^Ta linker moiety which is two separate residues of an amino acid or amino acid analogue and is independently a covalent bond, or is selected from C₁-C₆Aliphatic radical or C having 1 to 5 hetero atoms₁-C₆A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each R^cIndependently is-L^a-R′；

t is 0 to 50;

each L^aIndependently a covalent bond, or is selected from C₁-C₂₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₂₀A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each-Cy-is independently an optionally substituted divalent monocyclic, bicyclic, or polycyclic group, wherein each monocyclic ring is independently selected from C_3-20Cycloaliphatic Ring, C_6-20An aryl ring, a 5-to 20-membered heteroaryl ring having 1 to 10 heteroatoms, and a 3-to 20-membered heterocyclyl ring having 1 to 10 heteroatoms;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Each R is independently-H, or an optionally substituted group selected from: c _1-30Aliphatic radical, C having 1 to 10 heteroatoms_1-30Heteroaliphatic radical, C_6-30Aryl radical, C_6-30Arylaliphatic radical, C having 1 to 10 heteroatoms_6-30Aryl heteroaliphatic, 5-to 30-membered heteroaryl having 1 to 10 heteroatoms and 3-to 30-membered heterocyclyl having 1 to 10 heteroatoms, or

Optionally and independently, two R groups together form a covalent bond, or:

two or more R groups on the same atom optionally and independently form, together with the atom, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms in addition to the atom; or

Two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms in addition to the intervening atoms.

In some embodiments of the present invention, the,

is composed of

In some embodiments, each Xaa is independently an amino acid residue. In some embodiments, Xaa is an amino acid analog residue. In some embodiments, one or more Xaa are independently a natural amino acid residue. In some embodiments, one or more Xaa are independently an unnatural amino acid residue. In some embodiments, the side chains of two or more amino acid residues may be linked together to form a bridge. In some embodiments, R ^cAnd amino acid residue side chains may be linked together to form a bridge. In some embodiments, each bridge independently has L^a、L^bOr L^TThe structure of (1). In some embodiments, each bridge independently has L^aAnd (5) structure. In some embodiments, each bridge independently has L^bAnd (5) structure. In some embodiments, each bridge independently has L^TAnd (5) structure. For example, in some embodiments, the side chains of two cysteine residues may form a disulfide bridge comprising-S- (as in many proteins, it may be formed by two-SH groups). In some embodiments, R^cis-L^a-R, Xaa are residues of amino acids having the structure of formula A-I, wherein R^a2And R^a3One of them is R, and R^cR and R of^a2And R^a3Together form a covalent bond.

In some embodiments, - (Xaa) y-is or includes-Xaa^T1-Xaa^T2-(Xaa)y′-Xaa^T3-Xaa^T4-Xaa^T5-，

Wherein:

y' is 0 to 8;

Xaa^T1for C whose side chain is substituted₁-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T2including an optionally substituted aromatic group for its side chain or being optionally substituted C₃-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T3is C whose side chain is optionally substituted₂-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T4Including an optionally substituted aromatic group for its side chain or being optionally substituted C₃-C₈A residue of an amino acid or amino acid analog of an aliphatic group; and is

Xaa^T5For C whose side chain is substituted₁-C₈Aliphatic amino acids or amino acid analogues.

In some embodiments, y' is 0. In some embodiments, y' is 1. In some embodiments, y' is 2. In some embodiments, y' is 3. In some embodiments, y' is 4. In some embodiments, y' is 5. In some embodiments, y' is 6. In some embodiments, y' is 7. In some embodiments, y' is 8.

In some embodiments, Xaa^T1Including substituted C₁-C₈An aliphatic group. In some embodiments, Xaa^T1Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa^T1Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T1Has a side chain of C₂-C₈An alkyl group. In some embodiments, Xaa^T1Is or includes an optionally substituted linear C₂-C₈An alkyl group. In some embodiments, Xaa^T1Has a side chain of linear C₂-C₈An alkyl group. In some embodiments, the side chain is n-pentyl. In some embodiments, Xaa ^T1Is (S) -NH-CH (n-C)₅H₁₁) -C (O) -. In some embodiments, Xaa^T1Is or includes an aromatic groupAnd (4) clustering. In some embodiments, the side chain is-CH₂-R, wherein-CH₂-is optionally substituted, and R is optionally substituted aryl or heteroaryl. In some embodiments, the side chain is that of Y, W, S, K or K (MePEG4 c). In some embodiments, the side chain is that of Y, W or S. In some embodiments, Xaa^T1Is the residue of Y. In some embodiments, Xaa^T1Is the residue of W. In some embodiments, Xaa^T1Is the residue of S. In some embodiments, Xaa^T1Is the residue of K. In some embodiments, Xaa^T1Is the residue of K (MePEG4 c).

In some embodiments, Xaa^T2Is or includes an aromatic group. In some embodiments, Xaa^T2Side chain of (A) is-CH₂-R, wherein-CH₂-is optionally substituted, and R is as described herein. In some embodiments, R is optionally substituted aryl or heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-hydroxyphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, the side chain is that of Y or W. In some embodiments, Xaa^T2Is the residue of Y. In some embodiments, Xaa ^T2Is the residue of W. In some embodiments, Xaa^T2Is the residue of Bph. In some embodiments, Xaa^T2Including substituted C₁-C₈An aliphatic group. In some embodiments, Xaa^T2Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa^T2Is or includes optionally substituted C₃-C₈An aliphatic group. In some embodiments, Xaa^T2Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T2Has a side chain of C₂-C₈An alkyl group. In some embodiments, Xaa^T2Is or includes an optionally substituted linear C₂-C₈An alkyl group. In some embodiments, Xaa^T2Has a side chain of linear C₂-C₈An alkyl group. In some embodiments, Xaa^T2Has a side chain ofC of a branched chain₃-C₈An alkyl group. In some embodiments, the side chain is n-pentyl. In some embodiments, Xaa^T2Is (S) -NH-CH (n-C)₅H₁₁) -C (O) -. In some embodiments, the side chain is (CH)₃)₂CHCH₂-. In some embodiments, Xaa^T2Is a residue of L. In some embodiments, Xaa^T2Is the residue of A.

In some embodiments, Xaa^T3Including substituted C₁-C₈An aliphatic group. In some embodiments, Xaa^T3Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa ^T3Is or includes optionally substituted C₃-C₈An aliphatic group. In some embodiments, Xaa^T3Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T3Has a side chain of C₂-C₈An alkyl group. In some embodiments, Xaa^T3Is or includes an optionally substituted linear C₂-C₈An alkyl group. In some embodiments, Xaa^T3Has a side chain of linear C₂-C₈An alkyl group. In some embodiments, Xaa^T3The side chain of (A) is branched C₃-C₈An alkyl group. In some embodiments, the side chain is n-pentyl. In some embodiments, Xaa^T3Is the residue of Ahp. In some embodiments, the side chain is that of L, V or T. In some embodiments, Xaa^T3Is a residue of L. In some embodiments, Xaa^T3Is the residue of V. In some embodiments, Xaa^T3Is the residue of T. In some embodiments, Xaa^T3Including inclusion of two or more sp³A side chain of a carbon atom. In some embodiments, Xaa^T3Comprising a side chain comprising two or more groups, each of said groups independently being-CH₂-or-CH₃. In some embodiments, Xaa^T3Including, for example, -OH, -SO₂-and the like. In some embodiments, Xaa^T3Is the residue of Hse (homoserine). In some cases In the examples, Xaa^T3Is the residue of MetO2 (methionine sulfone).

In some embodiments, Xaa^T4Is or includes an aromatic group. In some embodiments, Xaa^T4Side chain of (A) is-CH₂-R, wherein-CH₂-is optionally substituted, and R is as described herein. In some embodiments, R is optionally substituted aryl or heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-hydroxyphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, the side chain is that of Y or W. In some embodiments, Xaa^T4Is the residue of Y. In some embodiments, Xaa^T4Is the residue of W. In some embodiments, Xaa^T4Is the residue of Bph. In some embodiments, Xaa^T4Including substituted C₁-C₈An aliphatic group. In some embodiments, Xaa^T4Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa^T4Is or includes optionally substituted C₃-C₈An aliphatic group. In some embodiments, Xaa^T4Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T4Has a side chain of C₂-C₈An alkyl group. In some embodiments, Xaa^T4Is or includes an optionally substituted linear C ₂-C₈An alkyl group. In some embodiments, Xaa^T4Has a side chain of linear C₂-C₈An alkyl group. In some embodiments, Xaa^T4The side chain of (A) is branched C₃-C₈An alkyl group. In some embodiments, the side chain is n-pentyl. In some embodiments, the side chain is isopropyl. In some embodiments, Xaa^T4Is the residue of V. In some embodiments, Xaa^T4Is the residue of Ahp.

In some embodiments, Xaa^T5Including substituted C₁-C₂₀An aliphatic group. In some embodiments, Xaa^T5Including substituted C₁-C₁₅An aliphatic group. At one endIn some embodiments, Xaa^T5Including substituted C₁-C₁₀An aliphatic group. In some embodiments, Xaa^T5Including substituted C₁-C₈An aliphatic group. In some embodiments, Xaa^T5Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa^T5Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T5Has a side chain of C₂-C₈An alkyl group. In some embodiments, Xaa^T5Is or includes an optionally substituted linear C₂-C₈An alkyl group. In some embodiments, Xaa^T5Has a side chain of linear C₂-C₈An alkyl group. In some embodiments, the side chain is n-pentyl. In some embodiments, Xaa^T5Is (S) -NH-CH (n-C)₅H₁₁) -C (O) -. In some embodiments, Xaa ^T5Is or includes an aromatic group. In some embodiments, the side chain is-CH₂-R, wherein-CH₂-is optionally substituted, and R is optionally substituted aryl or heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, the side chain is that of Y, W or S. In some embodiments, Xaa^T5Is the residue of Y. In some embodiments, Xaa^T5Is the residue of W. In some embodiments, Xaa^T5Is the residue of Bph. In some embodiments, Xaa^T5Is the residue of S. In some embodiments, Xaa^T5Is the residue of Ado. In some embodiments, Xaa^T5Is a residue of Ano. In some embodiments, Xaa^T5Is a residue of PhNle. In some embodiments, Xaa^T5Is a residue of PhNva.

In some embodiments, Xaa^T1Is or includes the side chain of Ahp or Y. In some embodiments, Xaa^T2Is or includes the side chain of Y, W, Ahp or Bph. In some embodiments, Xaa^T3Is or includes the side chain of L, C or Ahp. In some embodiments, Xaa^T4Has a side chain ofIncluding the side chain of Bph or V. In some embodiments, Xaa^T5The side chain of (b) is or includes a side chain of Ahp or Bph.

In some embodiments, Xaa^T1Is the residue of Ahp or Y. In some embodiments, Xaa^T2Y, W, Ahp or Bph. In some embodiments, Xaa^T3Residue L, C or Ahp. In some embodiments, Xaa^T4Is the residue of Bph or V. In some embodiments, Xaa^T5Residues of Ahp or Bph.

In some embodiments, - (Xaa) y-is or includes:

-(Xaa)_a1-(Xaa)_a2-(Xaa)_a3-(Xaa)_a4-(Xaa)_a5-(Xaa)_a6-(Xaa)_a7-(Xaa)_a8-(Xaa)_a9-(Xaa)_a10-(Xaa)_a11-(Xaa)_a12-(Xaa)_a13-，

wherein:

each of a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and a13 is independently 0 to 5;

(Xaa)_a3is or comprises Xaa^T1；

(Xaa)_a4Is or comprises Xaa^T2；

(Xaa)_a9Is or comprises Xaa^T3；

(Xaa)_a10Is or comprises Xaa^T4(ii) a And is

(Xaa)_a11Is or comprises Xaa^T5。

In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and/or a13 are independently 0. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and/or a13 are independently 1. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and/or a13 are independently 2. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and/or a13 are independently 3. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and/or a13 are independently 4. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and/or a13 are independently 5. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, a12, and a13 are 1.

In some embodiments, (Xaa)_a1Is or includes A. In some embodiments, a1 is 1, and (Xaa)_a1Is the residue of A. Other residues may also be utilized. For example, in some embodiments, (Xaa)_a1Is or includes K. In some embodiments, K is optionally linked to another moiety, such as an antibody binding moiety, via a linker. In some embodiments, (Xaa)_a1Is or includes K (MePEG4c) (CH bonded to an amino group in a side chain of K₃O(CH₂CH₂O)₃CH₂CH₂C (O) -; see the exemplary structures as described herein). In some embodiments, a1 is 0. In some embodiments, (Xaa)_a1Xaa (e.g., N-terminal residue) is linked to another Xaa (e.g., (Xaa)_a13Xaa of the C-terminal residue, etc.), as described herein. For example, in some embodiments, the N-terminal residue is linked to the C-terminal cysteine (e.g., -C (o) -CH) via its amino group, through a linker, via-S-of the C-terminal cysteine₂-, in which-C (O) -is bonded to an amino group, and-CH₂-is bonded to-S-.

In some embodiments, (Xaa)_a2Is or includes a residue whose side chain includes a heteroatom, OH or NH. In some embodiments, (Xaa)_a2Is or includes a residue comprising a polar or charged side chain. Other types of residues may also be utilized, such as residues comprising hydrophobic aliphatic side chains, e.g., a. In some embodiments, (Xaa) _a2Is or includes a residue whose side chain is: r, S, D, Y, A, W, K, 4Py2NH2((S) -2-amino-3- (2-aminopyridin-4-yl) propanoic acid), Cit (citrulline), F3G (3-guanidinophenylalanine), hCit (2-amino-5- (carbamoylamino) hexanoic acid; CAS: 201485-17-8), K (MePEG4c), RNdMe (N)⁵- [ (dimethylamino) iminomethyl]-L-ornithine; CAS: 1185841-84-2), RNMe (N⁵- [ imino (methylamino) methyl group]-acetate-L-ornithine; CAS: 1135616-49-7) or RNNdMe (N)⁵- [ (methylamino) (methylimino) methyl]-L-ornithine). In some embodiments, (Xaa)_a2Is or includes a residue having a side chain of R, S, D, Y, A or W. In some embodiments, (Xaa)_a2Is or includes a residue of R, S, D, Y, A, W, K, 4Py2NH2, Cit, F3G, hCit, K (MePEG4c), RNdMe, RNMe or RNNdMe. In some embodiments, (Xaa)_a2Is or includes residue R, S, D, Y, A or W. In some embodiments, (Xaa)_a2Is or includes R. In some embodiments, (Xaa)_a2Is or includes S. In some embodiments, (Xaa)_a2Is or includes D. In some embodiments, (Xaa)_a2Is or includes Y. In some embodiments, (Xaa)_a2Is or includes W. In some embodiments, (Xaa) _a2Is or includes A. In some embodiments, (Xaa)_a2Is or includes S. In some embodiments, (Xaa)_a2Is or includes K. In some embodiments, (Xaa)_a2Is or includes 4Py2NH 2. In some embodiments, (Xaa)_a2Is or includes Cit. In some embodiments, (Xaa)_a2Is or includes F3G. In some embodiments, (Xaa)_a2Is or includes hCit. In some embodiments, (Xaa)_a2Is or includes K (MePEG4 c). In some embodiments, (Xaa)_a2Is or includes RNdMe. In some embodiments, (Xaa)_a2Is or includes RNMe. In some embodiments, (Xaa)_a2Is or includes RNNdMe. In some embodiments, a2 is 1.

In some embodiments, a3 is 1. In some embodiments, (Xaa)_a3Is Xaa as described herein^T1。

In some embodiments, a4 is 1. In some embodiments, (Xaa)_a4Is Xaa as described herein^T2。

In some embodiments, (Xaa)_a5Is or comprises Xaa^T1. In some embodiments, (Xaa)_a5Is or includes a residue whose side chain includes an aromatic group. In some embodiments, (Xaa)_a5Is or includes a residue whose side chain includes a heteroatom, OH or NH.In some embodiments, (Xaa)_a5Is or includes a residue comprising a polar or charged side chain. Other types of residues may also be utilized, such as residues comprising hydrophobic aliphatic side chains, e.g., a. In some embodiments, (Xaa) _a5Is or includes a residue having a side chain of H, A, Y, S, L, W or W6N. In some embodiments, (Xaa)_a5Is or includes a residue having a side chain of H, A, Y, S, L or W. In some embodiments, (Xaa)_a5Is or includes residue H, A, Y, S, L, W or W6N. In some embodiments, (Xaa)_a5Is or includes residue H, A, Y, S, L or W. In some embodiments, (Xaa)_a5Is or includes H. In some embodiments, (Xaa)_a5Is or includes A. In some embodiments, (Xaa)_a5Is or includes Y. In some embodiments, (Xaa)_a5Is or includes S. In some embodiments, (Xaa)_a5Is or includes L. In some embodiments, (Xaa)_a5Is or includes W. In some embodiments, (Xaa)_a5Is or includes W6N. In some embodiments, a5 is 1.

In some embodiments, (Xaa)_a6Is or includes a residue comprising a polar or charged side chain. Other types of residues may also be utilized, such as residues comprising hydrophobic aliphatic side chains, e.g., a. In some embodiments, (Xaa)_a6Is or includes residues that do not include side chains. In some embodiments, (Xaa)_a6Is or includes a residue having a side chain of D, R, A or Y. In some embodiments, (Xaa) _a6Is or includes residue D, A, G, R or Y. In some embodiments, (Xaa)_a6Is or includes D. In some embodiments, (Xaa)_a6Is or includes A. In some embodiments, (Xaa)_a6Is or includes G. In some embodiments, (Xaa)_a6Is or includes R. In some embodiments, (Xaa)_a6Is or includes Y. In some embodiments, a6 is 1.

In some embodiments, (Xaa)_a7Is or includes a residue comprising a polar or charged side chain. Other types of residues may also be utilized, for example, residues comprising hydrophobic aliphatic side chainsSuch as a. In some embodiments, polar or charged amino acids may provide certain benefits, such as improved solubility for manufacturing, administration, delivery, activity, and the like. In some embodiments, (Xaa)_a7Is or includes residues that do not include side chains. In some embodiments, (Xaa)_a7Is or includes a residue whose side chain is that of MetO2 (methionine sulfone), D, R, A or Y. In some embodiments, (Xaa)_a7Is or includes a residue having a side chain of D, R, A or Y. In some embodiments, (Xaa)_a7Is or includes a residue having a side chain of D, R or S. In some embodiments, (Xaa)_a7Is or includes a residue having a side chain of D, E, N or Q. In some embodiments, (Xaa) _a7Is or includes a residue of MetO2, D, A, G, R, or Y. In some embodiments, (Xaa)_a7Is or includes residue D, A, G, R or Y. In some embodiments, (Xaa)_a7Is or includes residue D, E, N or Q. In some embodiments, (Xaa)_a7Is or includes residue D, G, R or S. In some embodiments, (Xaa)_a7Is or includes G. In some embodiments, (Xaa)_a7Is or includes MetO 2. In some embodiments, (Xaa)_a7Is or includes A. In some embodiments, (Xaa)_a7Is or includes D. In some embodiments, (Xaa)_a7Is or includes E. In some embodiments, (Xaa)_a7Is or includes Q. In some embodiments, (Xaa)_a7Is or includes N. In some embodiments, (Xaa)_a7Is or includes R. In some embodiments, (Xaa)_a7Is or includes S. In some embodiments, a7 is 1.

In some embodiments, (Xaa)_a8Is or includes a residue comprising a hydrophobic side chain. In some embodiments, (Xaa)_a8Is or includes a residue comprising an aliphatic side chain. In some embodiments, (Xaa)_a8Is or includes a residue having a side chain of V, D, G, W, S, T or A. In some embodiments, (Xaa)_a8Is or includes residue V, D, G, W, S, T or A. In some embodiments, (Xaa) _a8Is or includes V. In some embodiments, (Xa)a)_a8Is or includes D. In some embodiments, (Xaa)_a8Is or includes G. In some embodiments, (Xaa)_a8Is or includes W. In some embodiments, (Xaa)_a8Is or includes S. In some embodiments, (Xaa)_a8Is or includes T. In some embodiments, (Xaa)_a8Is or includes A. In some embodiments, a8 is 1.

In some embodiments, a9 is 1. In some embodiments, (Xaa)_a9Is Xaa as described herein^T3。

In some embodiments, a10 is 1. In some embodiments, (Xaa)_a10Is Xaa as described herein^T4。

In some embodiments, a11 is 1. In some embodiments, (Xaa)_a11Is Xaa as described herein^T5。

In some embodiments, (Xaa)_a12Is or includes a residue comprising a polar or charged side chain. In some embodiments, (Xaa)_a12Is or includes residues that do not include side chains. In some embodiments, (Xaa)_a12Is or includes a residue comprising a hydrophobic side chain. In some embodiments, (Xaa)_a12Is or includes a residue having a side chain of D, S, G, Ahp or A. In some embodiments, (Xaa)_a12Is or includes residue D, S, G, Ahp or A. In some embodiments, (Xaa)_a12Is or includes D. In some embodiments, (Xaa) _a12Is or includes S. In some embodiments, (Xaa)_a12Is or includes G. In some embodiments, (Xaa)_a12Is or includes Ahp. In some embodiments, (Xaa)_a12Is or includes A. In some embodiments, a12 is 1.

In some embodiments, (Xaa)_a13Is or includes a residue whose side chain includes a nucleophile. In some embodiments, (Xaa)_a13Is or includes a residue whose side chain includes-S-. In some embodiments, (Xaa)_a13Is or includes a residue having a side chain whose side chain is C. In some embodiments, (Xaa)_a13Is or includes a residue of C. In some embodiments, a13 is 1.In some embodiments, a13 is greater than 1, and the last residue is a residue whose side chain includes a nucleophile as described herein, e.g., C. In some embodiments, (Xaa)_a13Xaa (e.g., C-terminal residue) is linked to another Xaa (e.g., (Xaa)_a1Xaa of the C-terminal residue, etc.), as described herein. In some embodiments, it is linked via a linker, e.g., an LT as described herein. For example, in some embodiments, the C-terminal residue is linked to the N-terminal cysteine (e.g., -C (o) -CH) via its-S-, through a linker, via the amino group of the N-terminal cysteine ₂-, in which-C (O) -is bonded to an amino group, and-CH₂-is bonded to-S-. In some embodiments, a residue whose side chain includes-S- (e.g., a residue of C) is linked to an amino group of another residue (e.g., -C (o) -CH) via a linker₂-, in which-C (O) -is bonded to an amino group, and-CH₂-is bonded to-S-.

Exemplary sequences and data thereof include those described below:

larger values indicate binding. And (4) performing ELISA analysis.

In some embodiments, the target binding moiety or

As described above and/or as utilized in the compounds in table 1.

Is or comprise

Or a salt form thereof. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof.

In some embodiments, - (Xaa) y-is or includes-Xaa^T6-(Xaa)y′-Xaa^T7-Xaa^T8-Xaa^T9-Xaa^T10-Xaa^T11-，

Wherein:

y' is 0 to 8;

Xaa^T6for C whose side chain is substituted₁-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T7is C whose side chain is optionally substituted₂-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T8is a residue of proline or an amino acid analogue thereof;

Xaa^T9Including an optionally substituted aromatic group for its side chain or being optionally substituted C₁-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T10for C whose side chain is substituted₁-C₈A residue of an aliphatic group amino acid or an amino acid analog or a residue of an amino acid in which an amino group thereof is substituted; and is

Xaa^T11Including an optionally substituted aromatic group for its side chain or being optionally substituted C₁-C₈Aliphatic amino acids or amino acid analogues.

In some embodiments, Xaa^T6Are residues that include hydrophobic side chains. In some embodiments, Xaa^T6For which the side chain includes substituted C₁-C₈A residue of an aliphatic group. In some embodiments, the side chain is-CH₂-R, wherein-CH₂-is optionally substituted, and R is optionally substituted aryl or heteroaryl. In some embodiments, R is phenyl. In some embodiments, the side chain is-CH ₂Ph. In some embodiments, Xaa^T6Is an amino acid residue, and the amino group thereof is substituted. In some embodiments, the amino group is-N (R') -. In some embodiments, R' is optionally substituted C₁-C₆Alkyl radical. In some embodiments, R' is methyl. In some embodiments, the side chain is that of MeF (F (-N (Me))) L, or S where a methyl group is present on the N. In some embodiments, Xaa^T6is-N (Me) -CH (CH)₂Ph) -C (O) -. In some embodiments, Xaa^T6Is a residue of MeF, L or S.

In some embodiments, Xaa^T7Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa^T7Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T7Is or includes optionally substituted C₃-C₈An alkyl group. In some embodiments, Xaa^T7Is or includes optionally substituted C₄-C₈An alkyl group. In some embodiments, Xaa^T7Is or includes optionally substituted C₃-C₈A branched chain alkyl group. In some embodiments, Xaa^T7Is or includes optionally substituted C₄-C₈A branched chain alkyl group. In some embodiments, Xaa^T7The side chain of (A) is branched C₃-C₈An alkyl group. In some embodiments, Xaa^T7The side chain of (A) is branched C ₄-C₈An alkyl group. In some embodiments, the side chain is (CH)₃)₂CHCH₂-. In some embodiments, the side chain is a side chain of L. In some embodiments, Xaa^T7Is a residue of L.

In some embodiments, Xaa^T8Are residues that include cyclic moieties that participate in the backbone. In some embodiments, Xaa^T8Is P.

In some embodiments, Xaa^T9Is or includes an aromatic group. In some embodiments, Xaa^T9Side chain of (A) is-CH₂-R, wherein-CH₂-is optionally substituted, and R is as described herein. In some embodiments, R is optionally substituted aryl or heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-hydroxyphenyl. In some embodiments, R is 4-phenylphenyl. In some casesIn the examples, the side chain is that of Bph. In some embodiments, Xaa^T9Is the residue of Bph. In some embodiments, Xaa^T9Including substituted C₁-C₈An aliphatic group. In some embodiments, the substitution is a polar or charged group, such as-OH, -COOH, or the like. In some embodiments, the side chain is a side chain of D or S. In some embodiments, Xaa^T9Is a residue of D or S.

In some embodiments, Xaa^T10Is or includes substituted C ₁-C₈An aliphatic group. In some embodiments, Xaa^T10Is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, Xaa^T10Is or includes optionally substituted C₂-C₈An alkyl group. In some embodiments, Xaa^T10Has a side chain of C₂-C₈An alkyl group. In some embodiments, Xaa^T10Is or includes an optionally substituted linear C₂-C₈An alkyl group. In some embodiments, Xaa^T10Has a side chain of linear C₂-C₈An alkyl group. In some embodiments, Xaa^T10Is or includes an optionally substituted branched chain C₃-C₈An alkyl group. In some embodiments, Xaa^T10The side chain of (A) is branched C₃-C₈An alkyl group. In some embodiments, the side chain is (CH)₃)₂CH-. In some embodiments, the side chain is (CH)₃)₂CHCH₂-. In some embodiments, Xaa^T10Is the residue of V. In some embodiments, Xaa^T10Is a residue of L. In some embodiments, Xaa^T10Is an amino acid residue, and the amino group thereof is substituted. In some embodiments, the amino group is-N (R') -. In some embodiments, R' is optionally substituted C₁-C₆An alkyl group. In some embodiments, R' is methyl. In some embodiments, Xaa^T10Without side chains. In some embodiments, Xaa^T10is-N (Me) -CH₂-C(O)-。

In some embodiments, Xaa ^T11Is or a bagIncluding aromatic groups. In some embodiments, Xaa^T11Side chain of (A) is-CH₂-R, wherein-CH₂-is optionally substituted, and R is as described herein. In some embodiments, R is optionally substituted aryl or heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-hydroxyphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is optionally substituted

In some embodiments, R is

In some embodiments, the side chain is a side chain of W. In some embodiments, Xaa^T11Is the residue of W. In some embodiments, Xaa^T11Including substituted C₁-C₈An aliphatic group. In some embodiments, the substitution is a polar or charged group, such as-OH, -COOH, or the like. In some embodiments, the side chain is positively charged. In some embodiments, the side chain is that of R. In some embodiments, Xaa^T11Is the residue of R.

In some embodiments, Xaa^T6Is the residue of MeF. In some embodiments, Xaa^T7Is a residue of L. In some embodiments, Xaa^T8Is the residue of P. In some embodiments, Xaa^T9Is the residue of Bph. In some embodiments, Xaa^T10Is the residue of V. In some embodiments, Xaa ^T11Is the residue of W.

In some embodiments, - (Xaa) y-is or includes:

-(Xaa)_a1-(Xaa)_a2-(Xaa)_a3-(Xaa)_a4-(Xaa)_a5-(Xaa)_a6-(Xaa)_a7-(Xaa)_a8-(Xaa)_a9-(Xaa)_a10-(Xaa)a₁₁-(Xaa)_a12-，

wherein:

each of a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and a12 is independently 0 to 5;

(Xaa)_a4is or comprises Xaa^T6；

(Xaa)_a6Is or comprises Xaa^T7；

(Xaa)_a7Is or comprises Xaa^T8；

(Xaa)_a8Is or comprises Xaa^T9；

(Xaa)_a9Is or comprises Xaa^T10(ii) a And is

(Xaa)_a10Is or comprises Xaa^T11。

In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and/or a12 are independently 0. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and/or a12 are independently 1. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and/or a12 are independently 2. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and/or a12 are independently 3. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and/or a12 are independently 4. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and/or a12 are independently 5. In some embodiments, a1, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and a12 are 1.

In some embodiments, (Xaa)_a1Is or includes A. In some embodiments, a1 is 1, and (Xaa) _a1Is the residue of A. In some embodiments, a1 is 0. In some embodiments, (Xaa)_a1Xaa (e.g., N-terminal residue) is linked to another Xaa (e.g., (Xaa)_a13Xaa of the C-terminal residue, etc.), as described herein. For example, in some embodiments, the N-terminal residue is linked to the C-terminal cysteine (e.g., -C (o) -CH) via its amino group, through a linker, via-S-of the C-terminal cysteine₂-, in which-C (O) -is bonded to an amino group, and-CH₂-is bonded to-S-.

In some embodiments, (Xaa)_a2Is or comprises Xaa comprising a hydrophobic side chain^HAnd (c) a residue. In some embodiments, the side chain is-CH₃. In some embodiments, the side chain is (CH)₃)₂CHCH₂-. In some embodiments, Xaa is a residue of L. In some embodiments, Xaa is a residue of a. In some embodiments, Xaa is a residue of P. In some embodiments, (Xaa)_a2Is or includes L. In some embodiments, (Xaa)_a2Is or includes A. In some embodiments, (Xaa)_a2Is or includes P. In some embodiments, a2 is 1.

In some embodiments, Xaa^HThe side chain of (A) includes substituted C₁-C₈An aliphatic group. In some embodiments, the side chain is or includes optionally substituted C₂-C₈An aliphatic group. In some embodiments, the side chain is or includes optionally substituted C ₂-C₈An alkyl group. In some embodiments, the side chain is or includes optionally substituted C₃-C₈An alkyl group. In some embodiments, the side chain is or includes optionally substituted C₄-C₈An alkyl group. In some embodiments, the side chain is or includes optionally substituted C₃-C₈A branched chain alkyl group. In some embodiments, the side chain is or includes optionally substituted C₄-C₈A branched chain alkyl group. In some embodiments, the side chain is branched C₃-C₈An alkyl group. In some embodiments, the side chain is branched C₄-C₈An alkyl group. In some embodiments, the side chain is methyl. In some embodiments, the side chain is (CH)₃)₂CHCH₂-. In some embodiments, Xaa^HIs a residue of L. In some embodiments, Xaa^HIs the residue of A.

In some embodiments, (Xaa)_a3Is or includes a residue comprising a basic side chain (positively charged side chain). In some embodiments, the side chain of Xaa includes an optionally substituted aromatic basic moiety. In some embodiments, the side chain includes an optionally substituted imidazolyl group. In some embodiments, the side chain of Xaa includes an optionally substituted non-aromatic basic moiety. In some embodiments, the side chain comprises an optionally substituted guanidino group. In some embodiments, the side chain comprisesA substituted amino group is selected. Other types of residues may also be utilized, such as residues comprising hydrophobic aliphatic side chains, e.g., a. In some embodiments, the side chain is a side chain of H. In some embodiments, the side chain is that of R. In some embodiments, the side chain is that of a. In some embodiments, Xaa is a residue of H. In some embodiments, Xaa is the residue of R. In some embodiments, (Xaa) _a3Is or includes Xaa as described herein^HAnd (c) a residue. In some embodiments, Xaa is a residue of a. In some embodiments, (Xaa)_a3Is or includes H. In some embodiments, (Xaa)_a3Is or includes R. In some embodiments, (Xaa)_a3Is or includes A. In some embodiments, a3 is 1.

In some embodiments, (Xaa)_a4Is or comprises Xaa^T6. In some embodiments, a4 is 1. In some embodiments, (Xaa)_a4Is Xaa as described herein^T6. In some embodiments, (Xaa)_a4Is a residue of MeF or L. In some embodiments, (Xaa)_a4Is or includes MeF. In some embodiments, (Xaa)_a4Is or includes L. In some embodiments, a4 is 1.

In some embodiments, (Xaa)_a5Is or comprises Xaa^H. In some embodiments, (Xaa)_a5Is or includes C whose side chain is or includes optionally substituted₁-C₈Xaa of an aliphatic group. In some embodiments, the side chain is methyl. In some embodiments, Xaa is Xaa as described herein^T10. In some embodiments, Xaa is the residue of V. In some embodiments, Xaa is a residue of a. In some embodiments, Xaa is a residue of MeG (methyl on amino). In some embodiments, (Xaa)_a5Is or includes V. In some embodiments, (Xaa) _a5Is or includes A. In some embodiments, (Xaa)_a5Is or includes MeG. In some embodiments, a5 is 1.

In some embodiments, (Xaa)_a6As described herein (Xaa)_a2. In some embodiments, (Xaa)_a6Is or comprise a hydrophobic sideXaa of the chain^HAnd (c) a residue. In some embodiments, the side chain is-CH₃. In some embodiments, the side chain is (CH)₃)₂CHCH₂-. In some embodiments, Xaa is a residue of L. In some embodiments, Xaa is a residue of a. In some embodiments, Xaa is a residue of P. In some embodiments, (Xaa)_a6Is or includes L. In some embodiments, (Xaa)_a6Is or includes A. In some embodiments, (Xaa)_a6Is or includes P. In some embodiments, a6 is 1.

In some embodiments, (Xaa)_a6Is or comprises Xaa^T7. In some embodiments, a6 is 1. In some embodiments, (Xaa)_a6Is Xaa as described herein^T7. In some embodiments, (Xaa)_a6Is a residue of L or P.

In some embodiments, (Xaa)_a7Is or comprises Xaa^T8. In some embodiments, a7 is 1. In some embodiments, (Xaa)_a7Is Xaa as described herein^T8. In some embodiments, (Xaa)_a7Is the residue of P.

In some embodiments, (Xaa) _a8Is or comprises Xaa^T9. In some embodiments, a8 is 1. In some embodiments, (Xaa)_a8Is Xaa as described herein^T9. In some embodiments, (Xaa)_a8Is the residue of Bph. In some embodiments, (Xaa)_a8Is a residue of D or S.

In some embodiments, (Xaa)_a9Is or comprises Xaa^T10. In some embodiments, a9 is 1. In some embodiments, (Xaa)_a9Is Xaa as described herein^T10. In some embodiments, (Xaa)_a9V, L or MeG.

In some embodiments, (Xaa)_a10Is or comprises Xaa^T11. In some embodiments, a10 is 1. In some embodiments, (Xaa)_a10Is Xaa as described herein^T11. In some embodiments, (Xaa)_a10Is a residue of W or R.

In some embodiments, (Xaa)_a11Is or comprises Xaa^H. In some embodiments, (Xaa)_a11Is or includes C whose side chain is or includes optionally substituted₁-C₈Xaa of an aliphatic group. In some embodiments, the side chain is methyl. In some embodiments, the side chain is isopropyl. In some embodiments, Xaa is Xaa as described herein^T10. In some embodiments, Xaa is the residue of V. In some embodiments, Xaa is the residue of V. In some embodiments, Xaa is a residue of a. In some embodiments, Xaa is a residue of MeG (methyl on amino). In some embodiments, (Xaa) _a11Is or includes V. In some embodiments, (Xaa)_a11Is or includes A. In some embodiments, (Xaa)_a11Is or includes MeG. In some embodiments, a11 is 1.

In some embodiments, (Xaa)_a12Is or includes a residue whose side chain includes a nucleophile. In some embodiments, (Xaa)_a12Is or includes a residue whose side chain includes-S-. In some embodiments, (Xaa)_a12Is or includes a residue having a side chain whose side chain is C. In some embodiments, (Xaa)_a12Is or includes a residue of C. In some embodiments, a12 is 1. In some embodiments, a12 is greater than 1, and the last residue is a residue whose side chain includes a nucleophile as described herein, e.g., C. In some embodiments, (Xaa)_a12Xaa (e.g., C-terminal residue) is linked to another Xaa (e.g., (Xaa)_a1Xaa of the C-terminal residue, etc.), as described herein. For example, in some embodiments, the C-terminal residue is linked to the N-terminal cysteine (e.g., -C (o) -CH) via its-S-, through a linker, via the amino group of the N-terminal cysteine₂-, in which-C (O) -is bonded to an amino group, and-CH₂-is bonded to-S-. In some embodiments, a residue whose side chain includes-S- (e.g., a residue of C) is linked to an amino group of another residue (e.g., -C (o) -CH) via a linker ₂-, in which-C (O) -is bonded to an amino group, and-CH₂-is bonded to-S-.

Exemplary sequences and data thereof include those described below:

larger values indicate binding. And (4) performing ELISA analysis.

In some embodiments, the target binding moiety or

As described above and/or as utilized in the compounds in table 1. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof. In some embodiments of the present invention, the,

is or comprise

Or a salt form thereof.

In some embodiments, the target binding moiety or

Or- (Xaa) y-is or includes the following peptide:

(1) a polypeptide having an amino acid sequence represented by any one of SEQ ID nos. 1 to 34:

(2) a polypeptide having an amino acid sequence represented by any one of SEQ ID nos. 1 to 34, wherein the amino acid residue at the N-terminus is chloroacetylated (e.g., at the amino group thereof);

(3) a polypeptide having an amino acid sequence with a deletion, addition, substitution or insertion of one or more amino acids in any one of SEQ ID nos. 1-34, which does not include a deleted amino acid sequence having a Cys at the C-terminus in SEQ ID nos. 1-34;

(4) a polypeptide having an amino acid sequence represented by any one of SEQ ID nos. 1-34 having a deletion, addition, substitution, or insertion of one or more amino acids in any one of SEQ ID nos. 1-34, excluding a deleted amino acid sequence having a Cys at the C-terminus in any one of SEQ ID nos. 1-34, wherein the amino acid at the N-terminus is chloroacetylated (e.g., at its amino acid); or

(5) The polypeptide according to any one of (1) to (4) above, wherein the polypeptide has a cyclized structure.

In some embodiments, the target binding moiety or

Or- (Xaa) y-is or includes the following peptide:

(1) a polypeptide having an amino acid sequence represented by SEQ ID No.1 or 2:

Ala Arg Ahp Tyr His Asp Gly Val Leu Bph Ahp Asp Cys(SEQ ID NO.1)，

Ala Leu His MePhe Val Leu Pro Bph Val Trp Val Cys(SEQ ID NO.2)；

(2) a polypeptide having an amino acid sequence represented by SEQ ID No.1 or 2, wherein Ala at the N-terminus is chloroacetylated Ala;

(3) a polypeptide having a deletion, addition, substitution, or insertion of one or more amino acids in SEQ ID No.1 or 2 in the amino acid sequence, which does not include an amino acid sequence having a deletion of Cys at the C-terminus in SEQ ID No.1 or 2;

(4) a polypeptide having an amino acid sequence represented by SEQ ID No.1 or 2, wherein Ala at the N-terminus is chloroacetylated Ala, having a deletion, addition, substitution, or insertion of one or more amino acids in SEQ ID No.1 or 2, which excludes a deleted amino acid sequence having Cys at the C-terminus in SEQ ID No.1 or 2; or

In some embodiments, amino acid residues, e.g., at the N-terminus, such as Ala via-C (O) -CH ₂-is linked to Cys, wherein-C (O) -is bonded to Ala, and-CH₂-S-bonded to Cys. In some embodiments, the N-terminal amino acid residue (e.g., Ala) is attached by reacting a chloroacetylated amino acid residue (e.g., Ala) with-SH from Cys under suitable conditions.

In some embodiments, the amino acid substitution is a conservative substitution. In some embodiments, the substitution does not significantly affect the structure, properties, and/or activity of the peptide and/or protein. In some embodiments, examples of groups of amino acids whose side chains have similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic hydroxyl side chain: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chain: phenylalanine, tyrosine and tryptophan; 5) basic side chain: lysine, arginine and histidine; 6) acidic side chain: aspartic acid and glutamic acid; and 7) sulfur containing side chains: cysteine and methionine. In some embodiments, the conservative amino acid substitution is selected from valine-leucine-isoleucine, phenylalanine-tyrosine-tryptophan, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. The aforementioned amino acids may be proteinaceous or non-proteinaceous amino acids. Those skilled in the art will appreciate that, depending on the situation, amino acids may be grouped in other ways that are appropriate for the intended purpose based on structure, properties, activity, etc. In some embodiments, the present disclosure provides a target binding moiety that is or comprises an amino acid sequence having a deletion, substitution, insertion and/or addition of 1 to 5 amino acids, preferably 4 or less, 3 or less, 2 or less, more preferably one amino acid or less in the amino acid sequence represented by one of SEQ ID nos. 1 to 34 and that can bind to CD 38.

In some embodiments, the target binding moiety or

Is or includes a sequence represented by one of SEQ ID NO.1 to 34. In some embodiments, the target binding moiety is or comprises a cyclic structure.

In some embodiments, the target binding moiety is derived from, or

The following are: a structure selected from the following S-1 to S-32 (wherein SEQ ID No. of amino acid sequence is indicated) or a pharmaceutically acceptable salt thereof:

in some embodiments, the target binding moiety is derived from, or

The following are: a structure selected from the following S-33 to S-39 (wherein SEQ ID No. of amino acid sequence is indicated) or a pharmaceutically acceptable salt thereof:

in addition, various structures (e.g., S-1 to S-39) were assessed in various assays and shown to bind to CD 38.

As will be appreciated by those of skill in the art, structures (e.g., S-1 to S-39) can be attached to the remainder of the molecule (e.g., optionally via the antibody-binding portion of a linker) via a variety of suitable means in accordance with the present disclosure (e.g., via side chains (e.g., amino groups of certain side chains), N-termini, C-termini, etc.).

In some embodiments, the peptide unit, for example, has

Target binding moieties of structures orSalts thereof include functional groups in an amino acid residue that are reactive with functional groups of another amino acid residue. In some embodiments, a peptide unit comprises an amino acid residue having a side chain that includes a functional group that can react with another functional group of a side chain of another amino acid residue to form a bond (e.g., see moieties in table a-1, table 1, etc.). In some embodiments, one functional group of one amino acid residue is linked to a functional group of another amino acid residue to form a bond (or bridge). The bond is to the backbone atom of the peptide unit and does not include the backbone atom. In some embodiments, a peptide unit comprises a bond formed by two side chains of non-adjacent amino acid residues. In some embodiments, the bond is bonded to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, both backbone atoms bonded to the bond are carbon atoms. In some embodiments, the key has L ^bStructure of, wherein L^bIs L as described in this disclosure^aWherein L is^aNot a covalent bond. In some embodiments, L^aincluding-Cy-. In some embodiments, L^aincluding-Cy-wherein-Cy-is optionally substituted heteroaryl. In some embodiments, -Cy-is

In some embodiments, L^aIs composed of

In some embodiments, such L^aCan be derived from the side chain of an amino acid residue₃Formation of a group and a side chain of another amino acid residue. In some embodiments, the bond is formed via the attachment of two thiol groups, e.g., two cysteine residues. In some embodiments, L^aincluding-S-S-. In some embodiments, L^ais-CH₂-S-S-CH₂-. In some embodiments, the bond is via an amino group (e.g., -NH in the side chain of a lysine residue)₂) And a carboxylic acid group (e.g., -COOH in the side chain of an aspartic acid or glutamic acid residue). In some embodiments, L^acomprising-C (O) -N (R') -. In some embodiments，L^aincluding-C (O) -NH-. In some embodiments, L^ais-CH₂CONH-(CH₂)₃-. In some embodiments, L^aincluding-C (O) -N (R ') -, where R' is R, and forms a ring with the R group on the peptide backbone (e.g., as in A-34). In some embodiments, L^aIs- (CH)₂)₂-N(R′)-CO--(CH₂)₂-. In some embodiments, -Cy-is optionally substituted phenylene. In some embodiments, -Cy-is optionally substituted 1, 2-phenylene. In some embodiments, L ^aIs composed of

In some embodiments, L^aIs composed of

In some casesIn embodiments, the target binding moiety comprises a peptide unit, and the antibody binding moiety is attached to a backbone atom of the peptide unit, optionally via a linker. In some embodiments, the target binding moiety comprises a peptide unit, and the antibody binding moiety is attached to an atom of a side chain of an amino acid residue of the peptide unit, optionally via a linker, e.g. via an atom or group in the side chain. For example, in some embodiments, the antibody-binding moiety is via the side chain-SH, -OH, -COOH, or-NH ₂And (4) connecting.

Amino acids

In some embodiments, provided compounds and agents may comprise one or more amino acid moieties, for example in a universal antibody binding moiety, a linker moiety, and the like. The amino acid moiety can be a natural amino acid or an amino acid moiety of an unnatural amino acid. In some embodiments, the amino acid has the structure of formula a-I:

NH(R^a1)-L^a1-C(R^a2)(R^a3)-L^a2-COOH，

A-I

or a salt thereof, wherein each variable is independently as described in the disclosure. In some embodiments, for example, amino acid residues of amino acids having the structure of formulas A-I have-N (R)^a1)-L^a1-C(R^a2)(R^a3)-L^a2-CO-structure. In some embodiments, each amino acid residue in the peptide independently has-N (R)^a1)-L^a1-C(R^a2)(R^a3)-L^a2-CO-structure.

In some embodiments, L^a1Is a covalent bond. In some embodiments, the compounds of formula A-I have NH (R)^a1)-C(R^a2)(R^a3)-L^a2-COOH structure. In some embodiments, L^a2is-CH₂SCH₂-。

In some embodiments, L^a2Is a covalent bond. In some embodiments, the compounds of formula A-I have NH (R)^a1)-L^a1-C(R^a2)(R^a3) -COOH structure. In some embodiments, the amino acid residue has-N (R)^a1)-L^a1-C(R^a2)(R^a3) -CO-structure. In some embodiments, L^a1is-CH₂CH₂S-. In some embodiments, L^a1is-CH₂CH₂S-, in which CH₂Bonded to NH (R)^a1)。

In some embodiments, L^a1Is a covalent bond and L^a2Is a covalent bond. In some embodiments, the compounds of formula A-I have NH (R) ^a1)-C(R^a2)(R^a3) -COOH structure. In some embodiments, the compounds of formula A-I have NH (R)^a1)-CH(R^a2) -COOH structure. In some embodiments, the compounds of formula A-I have NH (R)^a1)-CH(R^a3) -COOH structure. In some embodiments, the compounds of formula a-I have NH₂-CH(R^a2) -COOH structure. In some embodiments, the compounds of formula a-I have NH₂-CH(R^a3) -COOH structure. In some embodiments, the amino acid residue has-N (R)^a1)-C(R^a2)(R^a3) -CO-structure. In some embodiments, the amino acid residue has-N (R)^a1)-CH(R^a2) -CO-structure. In some embodiments, the amino acid residue has-N (R)^a1)-CH(R^a3) -CO-structure. In some embodiments, the amino acid residue has an-NH-CH (R)^a2) -CO-structure. In some embodiments, the amino acid residue has an-NH-CH (R)^a3) -CO-structure.

In some embodiments, L^aIs a covalent bond. In some embodiments, L^aIs optionally substituted C_1-6A divalent aliphatic group. In some embodiments, L^aIs optionally substituted C_1-6An alkylene group. In some embodiments, L^ais-CH₂-. In some embodiments, L^ais-CH₂CH₂-. In some embodiments, L^ais-CH₂CH₂CH₂-。

In some embodiments, R' is R. In some embodiments, R^a1Is R, wherein R is as described in the disclosure. In some embodiments, R^a1Is R, wherein R is methyl. In some embodiments, R ^a2Is R, wherein R is as described in the disclosure. In some embodiments, R^a3Is R, wherein R is as described in the disclosure. In some embodiments, R^a1、R^a2And R^a3Each of which is independently R, wherein R is as described in the disclosure.

In some embodiments, R^a1Is hydrogen. In some embodiments, R^a2Is hydrogen. In some embodiments, R^a3Is hydrogen. In some embodiments, R^a1Is hydrogen, and R^a2And R^a3At least one of which is hydrogen. In some embodiments, R^a1Is hydrogen, R^a2And R^a3One of which is hydrogen and the other is not hydrogen. In some embodiments, R^a2is-L^a-R and R^a3is-H. In some embodiments, R^a3is-L^a-R and R^a2is-H. In some embodiments, R^a2is-CH₂-R and R^a3is-H. In some embodiments, R^a3is-CH₂-R and R^a2is-H. In some embodiments, R^a2Is R and R^a3is-H. In some embodiments, R^a3Is R and R^a2is-H.

In some embodiments, R^a2is-L^a-R, wherein R is as described in the disclosure. In some embodiments, R^a2is-L^a-R, wherein R is an optionally substituted group selected from: c_3-30Cycloaliphatic radical, C_5-30An aryl group, a 5-to 30-membered heteroaryl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-to 30-membered heterocyclyl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R ^a2is-L^a-R, wherein R is an optionally substituted group selected from: c_6-30Aryl, and 5 to 30 membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R^a2Is the side chain of an amino acid. In some embodiments, R^a2Are the side chains of standard amino acids.

In some embodiments of the present invention, the,R^a3is-L^a-R, wherein R is as described in the disclosure. In some embodiments, R^a3is-L^a-R, wherein R is an optionally substituted group selected from: c_3-30Cycloaliphatic radical, C_5-30An aryl group, a 5-to 30-membered heteroaryl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-to 30-membered heterocyclyl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R^a3is-L^a-R, wherein R is an optionally substituted group selected from: c_6-30Aryl, and 5 to 30 membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R^a3Is the side chain of an amino acid. In some embodiments, R^a3Are the side chains of standard amino acids.

In some embodiments, R is optionally substituted C_1-6An aliphatic group. In some embodiments, R is optionally substituted C _1-6An alkyl group. In some embodiments, R is-CH₃. In some embodiments, R is optionally substituted pentyl. In some embodiments, R is n-pentyl.

In some embodiments, R is a cyclic group. In some embodiments, R is optionally substituted C_3-30A cycloaliphatic radical. In some embodiments, R is cyclopropyl.

In some embodiments, R is an optionally substituted aromatic group and the amino acid residue of the amino acid of formula A-I is Xaa^A. In some embodiments, R^a2Or R^a3is-CH₂-R, wherein R is optionally substituted aryl or heteroaryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-trifluoromethylphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is an optionally substituted 5-to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a group having 1 to 5 substituents independently selected from oxygen,Optionally substituted 5-to 14-membered heteroaryl of nitrogen and sulfur heteroatoms. In some embodiments, R is

In some embodiments, R is optionally substituted pyridinyl. In some embodiments, R is 1-pyridyl. In some embodiments, R is 2-pyridyl. In some embodiments, R is 3-pyridyl. In some embodiments, R is

In some embodiments, R' is — COOH. In some embodiments, the compound of an amino acid residue of an amino acid of formula a-I is Xaa^N。

In some embodiments, R' is-NH₂. In some embodiments, the compound of an amino acid residue of an amino acid of formula a-I is Xaa^P。

In some embodiments, R^a2Or R^a3Is R, wherein R is C as described in the disclosure_1-20An aliphatic group. In some embodiments, the compound of an amino acid residue of an amino acid of formula a-I is Xaa^H. In some embodiments, R is-CH₃. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is n-propyl. In some embodiments, R is butyl. In some embodiments, R is n-butyl. In some embodiments, R is pentyl. In some embodiments, R is n-pentyl. In some embodiments, R is cyclopropyl.

In some embodiments, R^a1、R^a2And R^a3Two or more of which are R, and together form an optionally substituted ring as described in the disclosure.

In some embodiments, R^a1And R^a2And R^a3Are R and together form a radical other than R^a1An optionally substituted 3-to 6-membered ring having no additional ring heteroatoms beyond the nitrogen atom to which it is bonded. In some embodiments, the ring formed is a 5-membered ring, such as prolineIn (1).

In some embodiments, R^a2And R^a3Are R, and together form an optionally substituted 3-to 6-membered ring as described in the disclosure. In some embodiments, R^a2And R^a3Are R, and together form an optionally substituted 3-to 6-membered ring having one or more nitrogen ring atoms. In some embodiments, R^a2And R^a3Are R and together form an optionally substituted 3-to 6-membered ring having one and not more than one ring heteroatom which is a nitrogen atom. In some embodiments, the ring is a saturated ring.

In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is an unnatural amino acid. In some embodiments, the amino acid is an alpha-amino acid. In some embodiments, the amino acid is a β -amino acid. In some embodiments, the compounds of formula a-I are natural amino acids. In some embodiments, the compounds of formula a-I are unnatural amino acids.

In some embodiments, the amino acid comprises a hydrophobic side chain. In some embodiments, the amino acid having a hydrophobic side chain is A, V, I, L, M, F, Y or W. In some embodiments, the amino acid with a hydrophobic side chain is A, V, I, L, M or F. In some embodiments, the amino acid with a hydrophobic side chain is A, V, I, L or M. In some embodiments, the amino acid with a hydrophobic side chain is A, V, I or L. In some embodiments, the hydrophobic side chain is R, wherein R is C _1-10An aliphatic group. In some embodiments, R is C_1-10An alkyl group. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is butyl. In some embodiments, R is pentyl. In some embodiments, R is n-pentyl. In some embodiments, the amino acid with a hydrophobic side chain is NH₂CH(CH₂CH₂CH₂CH₂CH₃) COOH. In some embodiments, the amino acid having a hydrophobic side chain is (S) -NH₂CH(CH₂CH₂CH₂CH₂CH₃) COOH. In some embodiments, hydrophobicThe amino acid of the side chain is (R) -NH₂CH(CH₂CH₂CH₂CH₂CH₃) COOH. In some embodiments, the hydrophobic side chain is-CH₂R, wherein R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is phenyl substituted with one or more hydrocarbyl groups. In some embodiments, R is 4-phenylphenyl. In some embodiments, the amino acid with a hydrophobic side chain is NH₂CH(CH₂-4-phenylphenyl) COOH. In some embodiments, the amino acid having a hydrophobic side chain is (S) -NH₂CH(CH₂-4-phenylphenyl) COOH. In some embodiments, the amino acid having a hydrophobic side chain is (R) -NH₂CH(CH₂-4-phenylphenyl) COOH.

In some embodiments, the amino acid comprises a positively charged side chain as described herein (e.g., at physiological pH). In some embodiments, such amino acids include a basic nitrogen in the side chain. In some embodiments, such amino acid is Arg, His, or Lys. In some embodiments, such amino acid is Arg. In some embodiments, such amino acid is His. In some embodiments, such an amino acid is Lys.

In some embodiments, the amino acid comprises a negatively charged side chain as described herein (e.g., at physiological pH). In some embodiments, such amino acids include-COOH in the side chain. In some embodiments, such amino acid is Asp. In some embodiments, such amino acid is Glu.

In some embodiments, the amino acid comprises a side chain comprising an aromatic group as described herein. In some embodiments, such amino acid is Phe, Tyr, Trp, or His. In some embodiments, such amino acid is Phe. In some embodiments, such amino acid is Tyr. In some embodiments, such amino acid is Trp. In some embodiments, such amino acid is His. In some embodiments, such amino acid is NH₂-CH(CH₂-4-phenylphenyl) -COOH. In some embodiments, such amino acids are (S) -NH₂-CH(CH₂-4-phenylphenyl) -COOH. In some embodiments, such amino groupsThe acid being (R) -NH₂-CH(CH₂-4-phenylphenyl) -COOH.

In some embodiments, the amino acid is a known proteinogenic amino acid that is naturally encoded or found in the genetic code of any organism, or a non-proteinogenic amino acid that is not naturally encoded or found in the genetic code of any organism. Examples of non-proteinogenic amino acids include alpha, alpha-disubstituted amino acids (alpha-methylalanine, etc.), N-alkyl-alpha-amino acids, and N-alkyl-alpha-D-amino acids, and the backbone structure may differ from that of the natural type of amino acid. Examples of such amino acids include β -amino acids and amino acids having a side chain structure different from that of the natural type (e.g., norleucine, homohistidine and hydroxyproline).

In some embodiments, the amino acid is selected from:

bph beta- (4-biphenylyl) -alanine

MetO2 methionine sulfone

Hse homoserine

Har N6-carbamimidoyl-L-lysine

da D-alanine

W6N (S) -2-amino-3- (1H-pyrrolo [2, 3-c ] pyridin-3-yl) propionic acid

Ano (S) -2-aminononanoic acid

Ado (S) -2-aminoundecanoic acid

PhNle (S) -2-amino-6-phenylhexanoic acid

PhNva (S) -2-amino-5-phenylpentanoic acid

Nal2 (2-naphthyl) alanine

Cit citrulline

F3G 3-guanidinophenylalanine

RNMe N⁵- [ imino (methylamino) methyl group]-acetate-L-ornithine; CAS: 1135616-49-7

RNNdMe N⁵- [ (methylamino) (methylimino) methyl]-L-ornithine

RNdMe N⁵- [ (dimethylamino) imino groupMethyl radical]-L-ornithine; CAS: 1185841-84-2

hCit 2-amino-5- (carbamoylamino) hexanoic acid; CAS: 201485-17-8

4Py2NH2 (S) -2-amino-3- (2-aminopyridin-4-yl) propionic acid

Target

In some embodiments, the present disclosure provides techniques for selectively directing an agent comprising a target binding moiety (e.g., an ARM compound), an antibody, and an immune cell (e.g., an NK cell) to a desired target site comprising one or more targets. As will be appreciated by those skilled in the art, the provided techniques are applicable to various types of targets, including, in particular, targets of CD 38.

In some embodiments, the target is damaged or defective tissue. In some embodiments, the target is damaged tissue. In some embodiments, the target is a defective tissue. In some embodiments, the target is associated with a disease, disorder, or condition, such as cancer, a wound, and the like. In some embodiments, the target is a tumor. In some embodiments, the target is or comprises a diseased cell. In some embodiments, the target is or comprises a cancer cell. In some embodiments, the target is a foreign object. In some embodiments, the target is or comprises an infectious agent. In some embodiments, the target is a microorganism. In some embodiments, the target is or comprises a bacterium. In some embodiments, the target is or comprises a virus. In some embodiments, the target comprises or expresses CD 38.

In many embodiments, the target is a tissue and/or cell associated with a disease, disorder, or condition, in particular various types of cancer. In some embodiments, the target is or includes a cell associated with a condition, disorder, or disease. In some embodiments, the target is or comprises a cell associated with cancer. In some embodiments, the cell comprises or expresses CD 38. Furthermore, the present disclosure provides techniques that are particularly useful for selectively targeting cancer cells that include or express CD38 by the immune system via, for example, recruitment of antibodies (e.g., endogenous antibodies) and immune cells through the use of ARM.

The target site typically includes one or more physical, chemical, and/or biomarker, such as CD38, which may be utilized, for example, by a target binding portion of a provided compound (e.g., ARM) to selectively recruit antibodies and/or fragments thereof and/or immune cells to the target.

In some embodiments, the cells of the target site include one or more characteristic agents suitable for targeting CD38, for example. In some embodiments, such agents are proteins and/or fragments thereof. In some embodiments, such agents are antigens associated with a disease, disorder, or condition. In some embodiments, the target site and/or cells thereof comprise and/or express CD38, and the target binding moiety of the provided ARM can bind to CD 38.

Connector section

In some embodiments, the antibody binding moiety is optionally linked to the target binding moiety via a linker moiety. Various types and/or for various purposes of linker moieties may be utilized in accordance with the present disclosure, such as for antibody-drug conjugates and the like.

The linker moiety may be divalent or multivalent. In some embodiments, the linker moiety is divalent. In some embodiments, the linker is multivalent and connects more than two moieties.

In some embodiments, the linker moiety is L. In some embodiments, L is a covalent bond, or a divalent or multivalent optionally substituted straight or branched chain C comprising one or more aliphatic groups, aryl groups, heteroaliphatic groups having 1 to 20 heteroatoms, heteroaromatic groups having 1 to 20 heteroatoms, or any combination thereof_1-100A group wherein one or more methylene units of said group are optionally and independently replaced by: c_1-6Alkylene radical, C_1-6Alkenylene, divalent C with 1 to 5 heteroatoms_1-6Heteroaliphatic, -C.ident.C-, -Cy-, -C (R')₂-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-C(O)C(R′)₂N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R ') -, -C (O) S-, -C (O) O-, -P (O) -, -P (O) (SR') -, -P (O) (R ') -, -P (O) (NR') -, -P (S) (OR ') -, -P (S) (SR') -, -P (S) (R ') -, -P (S) (NR') -, -P (S ') -, -P (R') -, -P (OR ') -, -P (SR') -, -P (NR ') -, an amino acid residue OR- [ (-O-C (R'))₂-C(R′)₂-)_n]-, where n is 1 to 20. In some embodiments, each amino acid residue is independently a residue of an amino acid having the structure of formula a-I or a salt thereof. In some embodiments, each amino acid residue independently has-N (R)^a1)-L^a1-C(R^a2)(R^a3)-L^a2-CO-or a salt form thereof.

In some embodiments, L is divalent. In some embodiments, L is selected from C _1-100Aliphatic radical and C having 1 to 50 heteroatoms_1-100A divalent or optionally substituted straight or branched chain radical of a heteroaliphatic group, wherein one or more methylene units of said radical are optionally and independently replaced by: c_1-6Alkylene radical, C_1-6Alkenylene, divalent C with 1 to 5 heteroatoms_1-6Heteroaliphatic, -C.ident.C-, -Cy-, -C (R')₂-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-C(O)C(R′)₂N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R ') -, -C (O) S-, -C (O) O-, -P (O) -, -P (O) (SR') -, -P (O) (R ') -, -P (O) (NR') -, -P (S) (OR ') -, -P (S) (SR') -, -P (S) (R ') -, -P (S) (NR') -, -P (S ') -, -P (R') -, -P (OR ') -, -P (SR') -, -P (NR ') -, amino acid OR- [ (-O-C (R'))₂-C(R′)₂-)_n]-。

In some embodiments, L is a covalent bond. In some embodiments, L is a divalent optionally substituted straight or branched chain C_1-100An aliphatic group wherein one or more methylene units of said group are optionally and independently replaced. In some embodiments, L is a divalent optionally substituted straight or branched chain C_6-100Arylaliphatic group, wherein one or more methylene units of the group are optionally and independently replaced. In some implementationsIn one embodiment, L is a divalent optionally substituted straight or branched chain C having 1 to 20 heteroatoms _5-100Heteroarylaliphatic group, wherein one or more methylene units of said group are optionally and independently replaced. In some embodiments, L is a divalent optionally substituted straight or branched chain C having 1 to 20 heteroatoms_1-100A heteroaliphatic group, wherein one or more methylene units of the group are optionally and independently replaced.

In some embodiments, the linker moiety (e.g., L) is or includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) polyethylene glycol units. In some embodiments, the linker moiety is or comprises- (CR)₂CR₂O)_nWherein each of R and n is independently as described in the disclosure. In some embodiments, the linker moiety is or comprises- (CH)₂CH₂O)_n-, wherein n is as described in the present disclosure. In some embodiments, one or more methylene units of L are independently replaced by- (CH)₂CH₂O)_n-a permutation. In some embodiments, two or more methylene units of L are independently- (CR)₂CR₂O)_n-or- (CH)₂CH₂O)_n-a permutation. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

In some embodiments, - (CR) in the linker moiety, e.g., L₂CR₂Number of O) -cells or-(CH₂CH₂The number of O) -units is at least about 1 to 20, 2 to 20, 3 to 30, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20 or about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. In some embodiments, it is about or at least about 1. In some embodiments, it is about or at least about 2. In some embodiments, it is about or at least about 3. In some embodiments, it is about or at least about 4. In some embodiments, it is about or at least about 5. In some embodiments, it is about or at least about 6. In some embodiments, it is about or at least about 7. In some embodiments, it is about or at least about 8. In some embodiments, it is about or at least about 9. In some embodiments, it is about or at least about 10. In some embodiments, it is about or at least about 11. In some embodiments, it is about or at least about 12. In some embodiments, it is about or at least about 13. In some embodiments, it is about or at least about 14. In some embodiments, it is about or at least about 15. In some embodiments, it is about or at least about 16. In some embodiments, it is about or at least about 17. In some embodiments, it is about or at least about 18. In some embodiments, it is about or at least about 19. In some embodiments, it is about or at least about 20.

In some embodiments, a linker moiety (e.g., L) comprises one or more — (CR) as described herein₂CR₂O)_n-and/or- (CH)₂CH₂O)_n-and one or more amino acid residues.

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the connector sub-portion or L is or includes

In some embodiments, the linker moiety (e.g., L) is or includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acid residues. As used in this disclosure, "one or more"May be 1 to 100, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, 1 to 5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more. In some embodiments, one or more methylene units of L are independently replaced with an amino acid residue. In some embodiments, one or more methylene units of L are independently replaced with an amino acid residue, wherein the amino acid residue is an amino acid of formula a-I or a salt thereof. In some embodiments, one or more methylene units of L are independently replaced with an amino acid residue, wherein each amino acid residue independently has-N (R) ^a1)-L^a1-C(R^a2)(R^a3)-L^a2-CO-or a salt form thereof. In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is glycine. In some embodiments, the amino acid is an unnatural amino acid. In some embodiments, the amino acid is a D-amino acid. In some embodiments, the amino acid is beta-alanine. In some embodiments, the amino acid residue has a structure of-C (O) - (CH)₂CH₂O)n-CH₂CH₂NR '-or a salt form thereof, wherein n is 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and R' is as described herein. In some embodiments, n is 0. In some embodiments, n is 0 to 12. In some embodiments, n is 1 to 12. In some embodiments, R' is — H.

In some embodiments, linker moieties include one or more moieties, such as amino, carbonyl, and the like, that are available for linking to other moieties. In some embodiments, the linker moiety comprises one or more-NR '-, where R' is as described in the disclosure. In some embodiments, -NR' -improves solubility. In some embodiments, -NR' -acts as a point of attachment to another moiety. In some embodiments, R' is — H. In some embodiments, one or more methylene units of L are independently replaced with-NR '-wherein R' is as described in the disclosure.

In some embodiments, the linker moiety (e.g., L) comprises a-c (o) -group available for attachment to the moiety. In some embodiments, one or more methylene units of L are independently replaced with-c (o) -.

In some embodiments, the linker moiety (e.g., L) comprises an-NR' -group that is available for attachment to the moiety. In some embodiments, one or more methylene units of L are independently replaced by-N (R') -o.

In some embodiments, the linker moiety (e.g., L) comprises a-c (o) NR' -group that is available for attachment to the moiety. In some embodiments, one or more methylene units of L are independently replaced by-c (o) N (R') -L.

In some embodiments, the linker moiety (e.g., L) comprises-C (R')₂-a group. In some embodiments, one or more methylene units of L are independently replaced by-C (R')₂-a permutation. In some embodiments, -C (R')₂-is-CHR' -. In some embodiments, R' is- (CH)₂)₂C(O)NH(CH₂)₁₁COOH. In some embodiments, R' is- (CH)₂)₂COOH. In some embodiments, R' is — COOH.

In some embodiments, the linker moiety is or includes one or more cyclic moieties, e.g., one or more methylene units of L are replaced by-Cy-. In some embodiments, the linker moiety (e.g., L) comprises an aryl ring. In some embodiments, the linker moiety (e.g., L) comprises a heteroaryl ring. In some embodiments, the linker moiety (e.g., L) comprises an aliphatic ring. In some embodiments, the linker moiety (e.g., L) comprises a heterocyclyl ring. In some embodiments, the linker moiety (e.g., L) comprises multiple rings. In some embodiments, the loops in the linker moiety (e.g., L) are 3 to 20-membered. In some embodiments, the ring is 5-membered. In some embodiments, the ring is 6-membered. In some embodiments, the ring in the linker is the product of a cycloaddition reaction (e.g., click chemistry and variations thereof) used to link different moieties together.

In some embodiments, the connector sub-portion (e.g., L) is or includes

In some embodiments, the methylene unit of L is substituted with one or more substituents selected from the group consisting of alkyl, aryl, cycloalkyl, and heteroaryl

And (4) replacement. In some embodiments, -Cy-is

In some embodiments, the linker moiety (e.g., L) is or comprises-Cy-. In some embodiments, the methylene unit of L is replaced with-Cy-. In some embodiments, -Cy-is

In some embodiments, -Cy-is

In some embodiments, -Cy-is

In some embodiments, the linker moiety (e.g., L) in a provided agent (e.g., a compound in table 1) comprises

In some embodiments of the present invention, the,

in a structure of

In some embodiments of the present invention, the,

is composed of

In some embodiments of the present invention, the,

is composed of

In some embodiments, the connector sub-portions are as described in table 1. Additional connector sub-portions, for example, including for L²The described sub-portion of the connector. In some embodiments, L is L of the present disclosure¹. In some embodiments, L is L as described in this disclosure². In some embodiments, L is L as described in this disclosure³. In some embodiments, L is L as described in this disclosure^b。

In some embodiments, L is

In some embodiments, a linker comprises an amino acid sequence comprising one or more amino acid residues. In some embodiments, the linker is or comprises

In some embodiments, the linker is or comprises

In some embodiments, the linker is or includes a Gly residue. In some embodiments, the linker is or comprises- (Gly) n-, where n is as described herein. In some embodiments, n is 1 to 10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the linker is or comprises-Gly-. In some embodiments, the linker is or includes-Gly-. Without wishing to be bound by theory, in some embodiments, linkers comprising amino acid residues may provide various moieties that may facilitate, enhance, and/or enhance one or more properties and/or activitiesFractional hardness and/or orientation.

In some embodiments, the linker is linked to a moiety, such as a target binding moiety or an antibody binding moiety, via the N-terminal amino acid residue (e.g., via an amino group) or the C-terminal amino acid residue (e.g., via a-COOH group). In some embodiments, the linker is attached to the moiety via a side chain.

In some embodiments, the linker (e.g., L) is or includes divalent optionally substituted C_1-20An aliphatic group. In some embodiments, the linker (e.g., L) is or includes divalent optionally substituted C _1-20An alkylene group. In some embodiments, the divalent group is linear. In some embodiments, the linker (e.g., L) is or comprises a linear- (CH)₂)_n-, where n is 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20). In some embodiments, the linker (e.g., L) is or includes a linker having NHR' - (CH)₂)_n-a residue of an amino acid of the structure of-COOH or a salt thereof. In some embodiments, the linker (e.g., L) is or includes-NR' - (CH)₂)_n-CO-or a salt form thereof. In some embodiments, R' is — H. In some embodiments, as shown herein, the linker comprises an albumin binding moiety.

In some embodiments, as used herein (e.g., in various moieties), n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

In some embodiments, the linker is or includes a moiety, or fragment thereof, between two cyclic peptide moieties of a provided compound, e.g., in table 1.

Some embodiments of variables

For example, exemplary embodiments of variables are described throughout this disclosure. Embodiments of different variables may optionally be combined, as appreciated by those skilled in the art.

ABT is an antibody binding moiety as described herein, as defined above and described herein. In some embodiments, the ABT is an ABT of a compound selected from those depicted in table 1 below. In some embodiments, the ABT is a moiety selected from table a-1. In some embodiments, ABT is a moiety described in table 1.

In some embodiments, L is a bivalent or multivalent linker moiety linking one or more antibody binding moieties to one or more target binding moieties. In some embodiments, L is a bivalent linker moiety linking ABT and TBT. In some embodiments, L is a multivalent linker moiety linking ABT and TBT.

In some embodiments, L is a linker moiety of a compound selected from those depicted in table 1 below.

As defined above and described herein, TBT is a target binding moiety as described herein.

In some embodiments, the TBT is a target binding moiety of a compound selected from those depicted in table 1 below. In some embodiments, the TBT is a moiety selected from Table T-1. In some embodiments, the TBT is part described in table 1.

As defined above and described herein, R¹、R³And R⁵Each of which is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or from 1 to 5 independentlyAn 8-to 10-membered bicyclic heteroaromatic ring selected from a heteroatom of nitrogen, oxygen or sulfur; or: r¹And R¹' optionally together with its intervening carbon atoms form a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r³And R³' optionally together with its intervening carbon atoms form a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r bound to the same carbon atom ⁵Group and R⁵' the group optionally forms, together with its intervening carbon atoms, a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R⁵The radicals optionally forming C together with their intermediate atoms_1-10A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally substituted by-S-, -SS-, -N (R) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) N (R) -, -N (R) C (O) -, -S (O)₂-or-Cy¹-substitution, wherein each-Cy¹-independently is a 5-to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹Is hydrogen. In some embodiments, R¹Is an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R ¹Is optionally substituted C_1-6An aliphatic group. In some embodiments, R¹Is an optionally substituted 3-to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R¹Is optionally substituted phenyl. In some embodiments, R¹Is an optionally substituted 8-to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R¹Is an optionally substituted 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R¹Is an optionally substituted 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R¹Is an optionally substituted 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R ¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments, R¹And R¹' optionally together with their intervening carbon atoms form a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R¹And R¹' optionally together with their intervening carbon atoms form a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹Selected from those depicted in table 1 below.

In some embodiments, R is R as described in the disclosure¹. In some embodiments, R^a2Is R as described in this disclosure¹. In some embodiments, R^a3Is R as described in this disclosure¹。

In some embodiments, R³Is hydrogen. In some embodiments, R³Is an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R ³Is optionally substituted C_1-6An aliphatic group. In some embodiments, R³Is an optionally substituted 3-to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R³Is optionally substituted phenyl. In some embodiments, R³Is an optionally substituted 8-to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R³Is an optionally substituted 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R³Is an optionally substituted heteroatom having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfurA 5-to 6-membered monocyclic heteroaromatic ring. In some embodiments, R³Is an optionally substituted 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R³Is methyl. In some embodiments, R³Is composed of

In some embodiments, R³Is composed of

In some embodiments, R³Is composed of

In some embodiments, R³Is composed of

In some embodiments, R³Is composed of

Wherein the attachment site has (S) stereochemistry. In some embodiments, R³Is composed of

Wherein the attachment site has (R) stereochemistry. In some embodiments, R ³Is composed of

Wherein the attachment site has (R) stereochemistry.

In some embodiments, R³Is composed of

Wherein the attachment site has (R) stereochemistry.

In some embodiments, R³And R³' optionally together with their intervening carbon atoms form a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R³And R³' optionally together with their intervening carbon atoms form a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R³Selected from those depicted in table 1 below.

In some embodiments, R is R as described in the disclosure². In some embodiments, R^a2Is R as described in this disclosure². In some embodiments, R^a3Is R as described in this disclosure²。

In some embodiments, R⁵Is hydrogen. In some embodiments, R⁵Is an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R ⁵Is optionally substituted C_1-6An aliphatic group. In some embodiments, R⁵Is an optionally substituted 3-to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R⁵Is optionally substituted phenyl. In some embodiments, R⁵Is an optionally substituted 8-to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R⁵Is a compound having 1 to 2 independently selected nitrogen atomsOptionally substituted 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle of a heteroatom of oxygen or sulfur. In some embodiments, R⁵Is an optionally substituted 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R⁵Is an optionally substituted 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁵Is methyl. In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

Wherein the connecting position Dots have (S) stereochemistry. In some embodiments, R⁵Is composed of

Wherein the attachment site has (R) stereochemistry. In some embodiments, R⁵Is composed of

Wherein the attachment site has (S) stereochemistry. In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁴Is 5

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R⁵Is composed of

In some embodiments, R ⁴Is composed of

Wherein the attachment site has (S) stereochemistry. In some embodiments, R⁴Is composed of

Wherein the attachment site has (R) stereochemistry.

In some embodiments, R is attached to the same carbon atom⁵And R⁵The' group optionally forms a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring together with its intervening carbon atoms. In some embodiments, R is attached to the same carbon atom⁵And R⁵The' group optionally together with its intervening carbon atoms forms a compound having 1 to 2 substituents independently selected from nitrogenA 4-to 8-membered saturated or partially unsaturated spiroheterocyclic ring of a heteroatom of oxygen or sulfur.

In some embodiments, two R⁵The radicals together with their central atoms forming C_1-10A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally substituted by-S-, -SS-, -N (R) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) N (R) -, -N (R) C (O) -, -S (O)₂-or-Cy¹-substitution, wherein each-Cy¹-independently is a 5-to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, two R⁵The radicals together with their central atoms forming

In some embodiments, R⁵Selected from those depicted in table 1 below.

In some embodiments, R is R as described in the disclosure⁵. In some embodiments, R^a2Is R as described in this disclosure⁵. In some embodiments, R^a3Is R as described in this disclosure⁵。

As defined above and described herein, R¹′、R³' and R⁵Each of' is independently hydrogen or C_1-3An aliphatic group.

In some embodiments, R¹' is hydrogen. In some embodiments, R¹' is C_1-3An aliphatic group.

In some embodiments, R¹' is methyl. In some embodiments, R¹' is ethyl. In some embodiments, R¹' is n-propyl. In some embodiments, R¹' is isopropyl. In some embodiments, R¹' is cyclopropyl.

In some embodiments, R¹' is selected from those depicted in table 1 below.

In some embodiments, R³' is hydrogen. In some embodiments, R³' is C_1-3An aliphatic group.

In some embodiments, R³' is methyl. In some embodiments, R³' is ethyl. In some embodiments, R ³' is n-propyl. In some embodiments, R³' is isopropyl. In some embodiments, R³' is cyclopropyl.

In some embodiments, R³' is selected from those depicted in table 1 below.

In some embodiments, R⁵' is hydrogen. In some embodiments, R⁵' is C_1-3An aliphatic group.

In some embodiments, R⁵' is methyl. In some embodiments, R⁵' is ethyl. In some embodiments, R⁵' is n-propyl. In some embodiments, R⁵' is isopropyl. In some embodiments, R⁵' is cyclopropyl.

In some embodiments, R⁵' is selected from those depicted in table 1 below.

As defined above and described herein, R²、R⁴And R⁶Each of which is independently hydrogen or C_1-4An aliphatic group, or: r²And R¹Optionally together with their intermediate atoms form a 4-to 8-membered saturated ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfurOr a partially unsaturated monocyclic heterocycle; r⁴And R³Optionally together with their intermediate atoms, form a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R⁶Group and R adjacent thereto⁵The groups optionally form, together with their intermediate atoms, a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R²Is hydrogen. In some embodiments, R²Is C_1-4An aliphatic group. In some embodiments, R²Is methyl. In some embodiments, R²Is ethyl. In some embodiments, R²Is n-propyl. In some embodiments, R²Is isopropyl. In some embodiments, R²Is n-butyl. In some embodiments, R²Is an isobutyl group. In some embodiments, R²Is a tert-butyl group.

In some embodiments, R²And R¹Together with their intermediate atoms form a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R²And R¹Together with their central atoms form

In some embodiments, R²And R¹Together with their central atoms form

In some embodiments, R²Selected from those depicted in table 1 below.

In some embodiments, R⁴Is hydrogen. In some embodiments, R⁴Is C_1-4An aliphatic group. In some embodiments, R⁴Is methyl. In some embodiments, R⁴Is ethyl. In some embodiments, R⁴Is n-propyl. In some embodiments, R⁴Is isopropyl. In some embodiments, R⁴Is n-butyl. In some embodiments, R ⁴Is an isobutyl group. In some embodiments, R⁴Is a tert-butyl group.

In some embodiments, R⁴And R³Together with their intermediate atoms form a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁴And R³Together with their central atoms form

In some embodiments, R⁴And R³Together with their central atoms form

In some embodiments, R⁴Selected from those depicted in table 1 below.

In some embodiments, R⁶Is hydrogen. In some embodiments, R⁶Is C_1-4An aliphatic group. In some embodiments, R⁶Is methyl. In some embodiments, R⁶Is ethyl. In some embodiments, R⁶Is n-propyl. In some embodiments, R⁶Is isopropyl. In some embodiments, R⁶Is n-butyl. In some embodiments, R⁶Is an isobutyl group. In some embodiments, R⁶Is a tert-butyl group.

In some embodiments, R⁶Group and R adjacent thereto⁵The groups together with their intervening atoms form a 4-to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁶Group and R adjacent thereto⁵The radicals together with their central atoms forming

In some embodiments, R⁶Selected from those depicted in table 1 below.

In some embodiments, R is R as described in the disclosure¹'. In some embodiments, R^a2Is R as described in this disclosure¹'. In some embodiments, R^a3Is R as described in this disclosure¹'. In some embodiments, R is R as described in the disclosure³'. In some embodiments, R^a2Is R as described in this disclosure³'. In some embodiments, R^a3Is R as described in this disclosure³'. In some embodiments, R is R as described in the disclosure². In some embodiments, R^a2Is R as described in this disclosure². In some embodiments, R^a3Is R as described in this disclosure². In some embodiments, R is R as described in the disclosure⁴. In some embodiments, R^a2Is R as described in this disclosure⁴. In some embodiments, R^a3Is R as described in this disclosure⁴. In some embodiments, R is R as described in the disclosure⁶. In some embodiments, R^a2Is R as described in this disclosure⁶. In some embodiments, R ^a3Is R as described in this disclosure⁶。

As defined above and described herein, L¹To connect to

A trivalent linker moiety of (a).

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodimentsIn, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Is composed of

In some embodiments, L¹Selected from those depicted in table 1 below.

As defined above and described herein, L²Is a covalent bond or C_1-10A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 of said chainUp to 3 methylene units are independently and optionally substituted by-S-, -N (R) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) N (R) -, -N (R) C (O) -, -S (O) ₂-、

or-Cy¹-substitution, wherein each-Cy¹-independently is a 5-to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, L²Is a covalent bond. In some embodiments, L²Is C_1-10A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally substituted by-S-, -N (R) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) N (R) -, -N (R) C (O) -, -S (O)₂-、

In some embodiments, L²Is composed of

In some embodiments, L²Is composed of

In some embodiments, L²Is composed of

In some embodiments, L²Is composed of

In some embodiments, L²Is composed of

In some embodiments, L²Is composed of

In some embodiments, L²Selected from those depicted in table 1 below.

In some embodiments, L is L as described in this disclosure²。

TBT is a target binding moiety as defined above and described herein.

In some embodiments, the TBT is a target binding moiety.

In some embodiments, the TBT is

In some embodiments, the TBT is

In some embodiments, the TBT is selected from those depicted in table 1 below.

As defined above and described herein, each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

In some embodiments, m is selected from those depicted in table 1 below.

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

In some embodiments, n is selected from those depicted in table 1 below.

As defined above and described herein, R⁷Each of which is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: r bound to the same carbon atom ⁷Group and R⁷The' group optionally forms, together with its intervening carbon atoms, a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷Is hydrogen. In some embodiments, R⁷Is an optionally substituted group selected from: c_1-6An aliphatic group; a 3 to 8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a phenyl group; an 8 to 10 membered bicyclic aromatic carbocyclic ring; a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R⁷Is optionally substituted C_1-6An aliphatic group. In some embodiments, R⁷Is an optionally substituted 3-to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R⁷Is optionally substituted phenyl. In some embodiments, R⁷Is an optionally substituted 8-to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R ⁷Is an optionally substituted 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R⁷Is an optionally substituted 5-to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R⁷Is an optionally substituted 8-to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷Is methyl. In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R⁷Is composed of

In some embodiments, R ⁷Is composed of

In some embodiments, R is attached to the same carbon atom⁷Group and R⁷' the groups together with their intervening carbon atoms form a 3-to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R is attached to the same carbon atom⁷Group and R⁷The' group together with its intervening carbon atoms forms a 4-to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷Selected from those depicted in table 1 below.

As defined above and described herein, R⁷Each of' is independently hydrogen or C_1-3An aliphatic group.

In some embodiments, R⁷' is hydrogen. In some embodiments, R⁷' is methyl. In some embodiments, R⁷' is ethyl. In some embodiments, R⁷' is n-propyl. In some embodiments, R⁷' is isopropyl.

In some embodiments, R⁷' is selected from those depicted in table 1 below.

As defined above and described herein, R⁸Each of which is independently hydrogen or C_1-4An aliphatic group, or: r⁸Group and R adjacent thereto⁷The groups optionally form, together with their intermediate atoms, a 4-to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁸Is hydrogen. In some embodiments, R⁸Is C_1-4An aliphatic group. In some embodiments, R⁸Is methyl. In some embodiments, R⁸Is ethyl. In some embodiments, R⁸Is n-propyl. In some embodiments, R⁸Is isopropyl. In some embodiments, R⁸Is n-butyl. In some embodiments, R⁸Is an isobutyl group. In some embodiments, R⁸Is a tert-butyl group.

In some embodiments, R⁸Group and R adjacent thereto⁷The groups together with their intervening atoms form a 4-to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁸Group and R adjacent thereto⁷The radicals together with their central atoms forming

In some embodiments, R⁸Selected from those depicted in table 1 below.

As defined above and described herein, R⁹Is hydrogen, C_1-3Aliphatic radical or-C (O) C_1-3An aliphatic group.

In some embodiments, R⁹Is hydrogen. In some embodiments, R⁹Is C_1-3An aliphatic group. In some embodiments, R⁹is-C (O) C_1-3An aliphatic group.

In some embodiments, R ⁹Is methyl. In some embodiments, R⁹Is ethyl. In some embodiments, R⁹Is n-propyl. In some embodiments, R⁹Is isopropyl. In some embodiments, R⁹Is cyclopropyl. In some embodiments, R⁹is-C (O) Me. In some embodiments, R⁹is-C (O) Et. In some embodiments, R⁹is-C (O) CH₂CH₂CH₃. In some embodiments, R⁹is-C (O) CH (CH)₃)₂. In some embodiments, R⁹is-C (O) cyclopropyl.

In some embodiments, R⁹Selected from those depicted in table 1 below.

In some embodiments, R is R as described in the disclosure⁷. In some embodiments，R^a2Is R as described in this disclosure⁷. In some embodiments, R^a3Is R as described in this disclosure⁷. In some embodiments, R is R as described in the disclosure⁷'. In some embodiments, R^a2Is R as described in this disclosure⁷'. In some embodiments, R^a3Is R as described in this disclosure⁷'. In some embodiments, R is R as described in the disclosure⁸. In some embodiments, Ra²Is R as described in this disclosure⁸. In some embodiments, R^a3Is R as described in this disclosure⁸. In some embodiments, R is R as described in the disclosure ⁸'. In some embodiments, R^a2Is R as described in this disclosure⁸'. In some embodiments, R^a3Is R as described in this disclosure⁸'. In some embodiments, R is R as described in the disclosure⁹. In some embodiments, R^a2Is R as described in this disclosure⁹. In some embodiments, R^a3Is R as described in this disclosure⁹。

As defined above and described herein, L³To connect to

A divalent linker moiety to TBT.

In some embodiments, L³To connect to

A divalent linker moiety to TBT.

In some embodiments, L³Is composed of

In some embodiments, L³Is composed of

In some embodiments, L³Is composed of

In some embodiments, L³Is composed of

In some embodiments, L³Is composed of

In some embodiments, L³Is composed of

In some embodiments, L³Selected from those depicted in table 1 below.

In some embodiments, L is L as described in this disclosure³。

O is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 as defined above and described herein.

In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. In some embodiments, o is 6. In some embodiments, o is 7. In some embodiments, o is 8. In some embodiments, o is 9. In some embodiments, o is 10.

In some embodiments, o is selected from those depicted in table 1 below.

In certain embodiments, the present disclosure provides a compound of formula II, wherein L²Is composed of

And TBT is

Thereby forming a compound of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein L¹、R¹、R¹′、R²、R³、R³′、R⁴、R⁵、R⁵′、R⁶And each of m is as defined above and as described in the examples herein, individually and in combination.

And TBT is

Thereby forming a compound of formula II-b:

And TBT is

Thereby forming a compound of formula II-c:

And TBT is

Thereby forming a compound of formula II-d:

And TBT is

Thereby forming a compound of formula II-e:

or a pharmaceutically acceptable salt thereof, wherein L¹、R¹、R¹′、R²、R³、R³′、R⁴、R⁵、R⁵′、R⁶And each of mOne individually and in combination is as defined above and as described in the examples herein.

And TBT is

Thereby forming a compound of formula II-f:

In some embodiments, R^a1Is R as described in this disclosure. In some embodiments, R^a1Is optionally substituted C_1-4An aliphatic group. In some embodiments, R^a1Is optionally substituted C_1-4An alkyl group. In some embodiments, R^a1Is methyl.

In some embodiments, L^a1Is L as described in this disclosure^a. In some embodiments, L^a1Is a covalent bond.

In some embodiments, L^a2Is L as described in this disclosure^a. In some embodiments, L^a2Is a covalent bond.

In some embodiments, L^TIs L as described herein^a. In some embodiments, L^TIs L as described herein. In some embodiments, L ^TIs a covalent bond. In some embodiments, L^Tis-CH₂-C (O) -. In some embodiments, L^TTo the side chain-S- (e.g. via-CH)₂) With amino acid residues (e.g. via-C (O)).

In some embodiments, L^aIs a covalent bond. In some embodiments, L^aIs selected from C₁-C₁₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₁₀A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution. In some embodiments, L^aIs selected from C₁-C₅Aliphatic radical or C having 1 to 5 hetero atoms₁-C₅A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution. In some embodiments, L^aIs optionally substituted divalent C₁-C₅Aliphatic radical, in which one or more methylene units of the radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution. In some embodiments, L^aIs an optionally substituted divalent C1-C5 aliphatic group. In some embodiments, L^aIs an optionally substituted divalent C having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur ₁-C₅A heteroaliphatic group.

In some embodiments, R^a2Is R as described in this disclosure. In some embodiments, R^a2Is the side chain of natural amino acid. In some embodiments, R^a3Is R as described in this disclosure. In some embodiments, R^a3Is the side chain of natural amino acid. In some embodiments, R^2aAnd R^3aOne of which is hydrogen. In some embodiments, R^a2And/or R^a3Is R, wherein R is optionally substituted C_1-8Aliphatic or aryl groups. In some embodiments, R is optionally substituted linear C_2-8An alkyl group. In some embodiments, R is linear C_2-8An alkyl group. In some embodiments, R is an optionally substituted branched chain C_2-8An alkyl group. In some embodiments, R is a branched chain C_2-8An alkyl group. In some embodiments, R is n-pentyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted-CH₂-phenyl. In some embodiments, R is 4-phenylphenyl-CH₂-。

In some embodiments, each-Cy-is independently an optionally substituted divalent monocyclic, bicyclic, or polycyclic group, wherein each monocyclic ring is independently selected from: c_3-20A cycloaliphatic ring; c_6-20An aryl ring; a 5-to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3 to 20 membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, each-Cy-is independently an optionally substituted divalent group selected from: c _3-20A cycloaliphatic ring; c_6-20An aryl ring; a 5-to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3 to 20 membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy-is as in the present disclosure, e.g., for R and Cy^LOptionally substituted rings are described, but are divalent.

In some embodiments, -Cy-is monocyclic. In some embodiments, -Cy-is bicyclic. In some embodiments, -Cy-is polycyclic. In some embodiments, -Cy-is saturated. In some embodiments, -Cy-is partially unsaturated. In some embodiments, -Cy-is aromatic. In some embodiments, -Cy-comprises a saturated monocyclic moiety. In some embodiments, -Cy-comprises a partially unsaturated monocyclic moiety. In some embodiments, -Cy-comprises an aromatic monocyclic moiety. In some embodiments, -Cy-comprises a combination of saturated, partially unsaturated, and/or aromatic cyclic moieties. In some embodiments, -Cy-is or comprises a 3-membered ring. In some embodiments, -Cy-is or comprises a 4-membered ring. In some embodiments, -Cy-is or comprises a 5-membered ring. In some embodiments, -Cy-is or comprises a 6-membered ring. In some embodiments, -Cy-is or comprises a 7-membered ring. In some embodiments, -Cy-is or comprises an 8-membered ring. In some embodiments, -Cy-is or includes a 9-membered ring. In some embodiments, -Cy-is or comprises a 10-membered ring. In some embodiments, -Cy-is or comprises an 11-membered ring. In some embodiments, -Cy-is or includes a 12-membered ring. In some embodiments, -Cy-is or comprises a 13-membered ring. In some embodiments, -Cy-is or comprises a 14-membered ring. In some embodiments, -Cy-is or comprises a 15-membered ring. In some embodiments, -Cy-is or comprises a 16-membered ring. In some embodiments, -Cy-is or comprises a 17-membered ring. In some embodiments, -Cy-is or comprises an 18-membered ring. In some embodiments, -Cy-is or comprises a 19-membered ring. In some embodiments, -Cy-is or comprises a 20-membered ring.

In some embodiments, -Cy-is or includes an optionally substituted divalent C_3-20A cycloaliphatic ring. In some embodiments, -Cy-is or includes an optionally substituted divalent saturated C_3-20A cycloaliphatic ring. In some embodiments, -Cy-is or includes an optionally substituted divalent moiety unsaturated C_3-20A cycloaliphatic ring. In some embodiments, -Cy-H is an optionally substituted cycloaliphatic as described in the present disclosure, e.g., a cycloaliphatic example of R.

In some embodiments, -Cy-is or includes optionally substituted C_6-20An aryl ring. In some embodiments, -Cy-is or includes optionally substituted phenylene. In some embodiments, -Cy-is or includes optionally substituted 1, 2-phenylene. In some embodiments, -Cy-is or includes optionally substituted 1, 3-phenylene. In some embodiments, -Cy-is or includes being optionally takenSubstituted 1, 4-phenylene. In some embodiments, -Cy-is or includes an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an optionally substituted aryl as described in this disclosure, e.g., an aryl embodiment of R.

In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heteroaryl ring having one heteroatom independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-H is heteroaryl optionally substituted as described in this disclosure, e.g., heteroaryl embodiments of R. In some embodiments, -Cy-is

In some embodiments, -Cy-is or includes an optionally substituted divalent 3-to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy-is or includes an optionally substituted divalent 3-to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 3-to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heterocyclyl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heterocyclyl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted divalent 5-to 6-membered heterocyclyl ring having one heteroatom independently selected from oxygen, nitrogen, sulfur. In some embodiments, -Cy-is or includes an optionally substituted saturated divalent heterocyclic group. In some embodiments, -Cy-is or includes an optionally substituted partially unsaturated divalent heterocyclic group. In some embodiments, -Cy-H is an optionally substituted heterocyclyl as described in this disclosure, e.g., heterocyclyl embodiments of R.

In some embodiments, -Cy-is

In some embodiments, -Cy-is

In some embodiments, -Cy-is

In some embodiments, -Cy-is

In some embodiments, -Cy-is

In some embodiments, each Xaa is independently an amino acid residue. In some embodiments, each Xaa is independently an amino acid residue of an amino acid of formula a-I.

In some embodiments, t is 0. In some embodiments, t is 1 to 50. In some embodiments, t is z as described in this disclosure.

In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, y is 10. In some embodiments, y is 11. In some embodiments, y is 12. In some embodiments, y is 13. In some embodiments, y is 14. In some embodiments, y is 15. In some embodiments, y is 16. In some embodiments, y is 17. In some embodiments, y is 18. In some embodiments, y is 19. In some embodiments, y is 20. In some embodiments, y is greater than 20.

In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, z is 20. In some embodiments, z is greater than 20.

In some embodiments, R^cIs R' as described in this disclosure. In some embodiments, R^cIs R as described in this disclosure. In some embodiments, R^cis-N (R')₂Wherein each R' is independently as described in the disclosure. In some embodiments, R^cis-NH₂. In some embodiments, R^cIs R-C (O) -, wherein R is as described in the disclosure. In some embodiments, R ^cis-H.

In some embodiments, a is 1. In some embodiments, a is 2 to 100. In some embodiments, a is 5. In some embodiments, a is 10. In some embodiments, a is 20. In some embodiments, a is 50.

In some embodiments, b is 1. In some embodiments, b is 2 to 100. In some embodiments, b is 5. In some embodiments, b is 10. In some embodiments, b is 20. In some embodiments, b is 50.

In some embodiments, a1 is 0. In some embodiments, a1 is 1.

In some embodiments, a2 is 0. In some embodiments, a2 is 1.

In some embodiments, L^bIs L as described in this disclosure^a. In some embodiments, L^bincluding-Cy-. In some embodiments, L^bIncluding double bonds. In some embodiments, L^bincluding-S-. In some embodiments, L^bincluding-S-S-. In some embodiments, L^bcomprising-C (O) -N (R') -.

In some embodiments, R' is-R, -C (O) OR, OR-S (O)₂R, wherein R is as described in the disclosure. In some embodiments, R' is R, wherein R is as described in the disclosure. In some embodiments, R' is-c (o) R, wherein R is as described in the disclosure. In some embodiments, R' is-c (o) OR, wherein R is as described in the disclosure. In some embodiments, R' is-S (O) ₂R, wherein R is as described in the disclosure. In some embodiments, R' is hydrogen. In some embodiments, R' is not hydrogen. In some embodiments, R' is R, wherein R is optionally substituted C as described in the disclosure_1-20An aliphatic group. In some embodiments, R' is R, wherein R is optionally substituted C as described in the disclosure_1-20A heteroaliphatic group. In some embodiments, R' is R, wherein R is optionally substituted C as described in the disclosure_6-20And (4) an aryl group. In some embodiments, R' is R, wherein R is optionally substituted C as described in the disclosure_6-20An arylaliphatic group. In some embodiments, R' is R, wherein R is optionally substituted C as described in the disclosure_6-20An aryl heteroaliphatic group. In some embodiments, R' is R, wherein R is optionally taken as described in the disclosureSubstituted 5 to 20 membered heteroaryl. In some embodiments, R' is R, wherein R is an optionally substituted 3-to 20-membered heterocyclyl as described in this disclosure. In some embodiments, two or more R' are R, and optionally and independently together form an optionally substituted ring as described in the present disclosure.

In some embodiments, each R is independently-H, or an optionally substituted group selected from: c _1-30An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-30A heteroaliphatic group; c_6-30An aryl group; c_6-30An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-30An aryl heteroaliphatic group; a 5-to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3-to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

Optionally and independently, two R groups together form a covalent bond, or:

In some embodiments, each R is independently-H, or an optionally substituted group selected from: c _1-30An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-30A heteroaliphatic group; c_6-30An aryl group; c_6-30An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-30An aryl heteroaliphatic group; having 1 to 10 substituents independently selected from oxygen, nitrogen5-to 30-membered heteroaryl of heteroatoms of sulfur, phosphorus and silicon; and a 3-to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

Optionally and independently, two R groups together form a covalent bond, or:

two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, each R is independently-H, or an optionally substituted group selected from: c _1-20An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-20A heteroaliphatic group; c_6-20An aryl group; c_6-20An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-20An aryl heteroaliphatic group; a 5-to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3-to 20-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

Optionally and independently, two R groups together form a covalent bond, or:

two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 20-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

Two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 20-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, each R is independently-H, or an optionally substituted group selected from: c _1-30An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-30A heteroaliphatic group; c_6-30An aryl group; c_6-30An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-30An aryl heteroaliphatic group; a 5-to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3-to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, each R is independently-H, or an optionally substituted group selected from: c_1-20An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-20A heteroaliphatic group; c_6-20An aryl group; c_6-20An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-20An aryl heteroaliphatic group; a 5-to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3-to 20-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is an optionally substituted group selected from: c _1-30An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-30A heteroaliphatic group; c_6-30An aryl group; a 5-to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3 to 30 membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, R is hydrogen or an optionally substituted group selected from: c_1-20An aliphatic group; a phenyl group; a 3 to 7 membered saturated or partially unsaturated carbocyclic ring; 8 to 10 yuanA saturated, partially unsaturated, or aryl ring; a 5-to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is optionally substituted C_1-30An aliphatic group. In some embodiments, R is optionally substituted C_1-20An aliphatic group. In some embodiments, R is optionally substituted C _1-15An aliphatic group. In some embodiments, R is optionally substituted C_1-10An aliphatic group. In some embodiments, R is optionally substituted C_1-6An aliphatic group. In some embodiments, R is optionally substituted C_1-6An alkyl group. In some embodiments, R is optionally substituted hexyl, pentyl, butyl, propyl, ethyl, or methyl. In some embodiments, R is an optionally substituted hexyl. In some embodiments, R is optionally substituted pentyl. In some embodiments, R is optionally substituted butyl. In some embodiments, R is optionally substituted propyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is hexyl. In some embodiments, R is pentyl. In some embodiments, R is butyl. In some embodiments, R is propyl. In some embodiments, R is ethyl. In some embodiments, R is methyl. In some embodiments, R is isopropyl. In some embodiments, R is n-propyl. In some embodiments, R is tert-butyl. In some embodiments, R is sec-butyl. In some embodiments, R is n-butyl. In some embodiments, R is- (CH) ₂)₂CN。

In some embodiments, R is optionally substituted C_3-30A cycloaliphatic radical. In some embodiments, R is optionally substituted C_3-20A cycloaliphatic radical. In some embodiments of the present invention, the,r is optionally substituted C_3-10A cycloaliphatic radical. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

In some embodiments, R is an optionally substituted 3-to 30-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cycloheptyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

In some embodiments, when R is or includes a ring structure, such as a cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, and the like, the ring structure can be monocyclic, bicyclic, or polycyclic. In some embodiments, R is or comprises a monocyclic structure. In some embodiments, R is or includes a bicyclic structure. In some embodiments, R is or comprises a polycyclic structure.

In some embodiments, R is a group having 1 to 10 substituents independently selected from oxygen, nitrogen, sulfur, phosphorus, andoptionally substituted C of hetero atoms of silicon_1-30A heteroaliphatic group. In some embodiments, R is optionally substituted C having 1 to 10 heteroatoms_1-20A heteroaliphatic group. In some embodiments, R is optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, or silicon_1-20A heteroaliphatic group, optionally comprising one or more oxidized forms of nitrogen, sulfur, phosphorus, or selenium. In some embodiments, R is optionally substituted C comprising 1 to 10 groups independently selected from_1-30Heteroaliphatic group:

-N＝、≡N、-S-、-S(O)-、-S(O)₂-、-O-、＝O、

in some embodiments, R is optionally substituted C_6-30And (4) an aryl group. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is substituted phenyl.

In some embodiments, R is an optionally substituted 8-to 10-membered bicyclic saturated, partially unsaturated, or aryl ring. In some embodiments, R is an optionally substituted 8-to 10-membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8-to 10-membered bicyclic moiety unsaturated ring. In some embodiments, R is an optionally substituted 8-to 10-membered bicyclic aryl ring. In some embodiments, R is optionally substituted naphthyl.

In some embodiments, R is an optionally substituted 5-to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5-to 30-membered heteroaryl ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R is an optionally substituted 5-to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5-to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, R is a substituted 5-to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-to 6-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.

In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted pyrrolyl, furanyl, or thienyl.

In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom and an additional heteroatom selected from sulfur or oxygen. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having four nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having three nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having two nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring having one nitrogen atom.

In certain embodiments, R is an optionally substituted 8-to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5, 6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6, 6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is a 3-to 30-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3 to 30 membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is a 3-to 30-membered heterocyclic ring having 1-to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3 to 30 membered heterocyclic ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R is an optionally substituted 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-to 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-to 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-membered heterocyclic ring having one heteroatom selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 4-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-to 6-membered partially unsaturated monocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted tetrahydropyridinyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl.

In some embodiments, R is an optionally substituted 7-to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted indolinyl. In some embodiments, R is optionally substituted isoindolinyl. In some embodiments, R is an optionally substituted 1, 2, 3, 4-tetrahydroquinolinyl. In some embodiments, R is optionally substituted 1, 2, 3, 4-tetrahydroisoquinolinyl. In some embodiments, R is optionally substituted azabicyclo [3.2.1] octyl.

In some embodiments, R is an optionally substituted 8-to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5, 6-fused heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is optionally substituted C_6-30An arylaliphatic group. In some embodiments, R is optionally substituted C_6-20An arylaliphatic group. In some embodiments, R is optionally substituted C_6-10An arylaliphatic group. In some embodiments, the aryl portion of the arylaliphatic has 6, 10, or 14 aryl carbon atoms. In some embodiments, the aryl portion of the arylaliphatic has 6 aryl carbon atoms. In some embodiments, the aryl portion of the arylaliphatic group has 10 aryl carbon atoms. In some embodiments, the aryl portion of the arylaliphatic group has 14 aryl carbon atoms. In some embodiments, the aryl moiety is optionally substituted phenyl.

In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-30An aryl heteroaliphatic group. In some embodiments, R is a heteroatom having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur Optionally substituted C of_6-30An aryl heteroaliphatic group. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-20An aryl heteroaliphatic group. In some embodiments, R is optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur_6-20An aryl heteroaliphatic group. In some embodiments, R is optionally substituted C having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-10An aryl heteroaliphatic group. In some embodiments, R is optionally substituted C having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur_6-10An aryl heteroaliphatic group.

In some embodiments, two R groups optionally and independently form a covalent bond together. In some embodiments, -C ═ O is formed. In some embodiments, -C ═ C-is formed. In some embodiments, -C ≡ C-is formed.

In some embodiments, two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 20-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 10-membered monocyclic, bicyclic, or polycyclic ring having 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 6-membered monocyclic, bicyclic, or polycyclic ring having 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form, with the atom, an optionally substituted 3-to 5-membered monocyclic, bicyclic, or polycyclic ring having 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom.

In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 20-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 10-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 10-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 6-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with their intervening atoms, an optionally substituted 3-to 5-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

In some embodiments, the heteroatoms in the R groups or in the structures formed by two or more R groups together are selected from oxygen, nitrogen, and sulfur. In some embodiments, the formed ring is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially saturated. In some embodiments, the ring formed is aromatic. In some embodiments, the formed ring comprises a saturated, partially saturated, or aromatic ring moiety. In some embodiments, the ring formed comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the formed contains no more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the aromatic ring atoms are selected from carbon, nitrogen, oxygen, and sulfur.

In some embodiments, the ring formed by two or more R groups (or two or more groups selected from R and variables that can be R) taken together is C_3-30A cycloaliphatic group; c _6-30An aryl group; a 5-to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or a 3-to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, such as the rings described for R, but which is divalent or polyvalent.

Exemplary compounds are set forth in table 1 below.

TABLE 1 exemplary Compounds

In some embodiments, the present disclosure provides a compound set forth in table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-3, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-4 or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides compound I-5 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-6 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-8, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-9, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-10, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-11, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-12, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-13, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-14 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-15, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-16, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-17 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-18, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-19, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-24, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-25, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-26, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-27, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-28, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-29, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-30, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-31 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-32, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-33, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-34, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-35, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-36, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-37 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-38, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-39, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-40, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-41, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-42, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-43, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-44, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-45, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-46 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compound I-47, or a pharmaceutically acceptable salt thereof.

4. General methods for providing the Compounds of the invention

The compounds of the present disclosure may generally be prepared or isolated by synthetic and/or semi-synthetic methods known to those of skill in the art for analogous compounds and by the methods described in detail in the examples herein.

In some embodiments, where particular protecting groups ("PG"), leaving groups ("LG"), or conversion conditions are depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and conversion conditions are also suitable and encompassed. The groups and transformations are described in detail in the machester advanced organic chemistry: reactions, Mechanisms and structures (March's Advanced Organic Chemistry: Reactions, mechanics, and Structure), M.B.Smith and J.March, 5 th edition, John Willi-parent-child publishing, 2001; comprehensive Organic Transformations (Comprehensive Organic Transformations), r.c. larock, 2 nd edition, john wiley parent-child publishing company, 1999; and Protecting Groups in Organic Synthesis (Protecting Groups in Organic Synthesis), t.w.greene and p.g.m.wuts, 3 rd edition, john wily parent-son publishing company, 1999, the entire contents of each of which are hereby incorporated by reference herein.

In some embodiments, the leaving group comprises, but is not limited to, a halogen (e.g., fluoride, chloride, bromide, iodide), a sulfonate (e.g., methanesulfonate, toluenesulfonate, benzenesulfonate, bromobenzenesulfonate, nitrobenzenesulfonate, trifluoromethanesulfonate), diazonium, and the like.

In some embodiments, the oxygen protecting group comprises, for example, a carbonyl protecting group, a hydroxyl protecting group, and the like. Hydroxy protecting groups are well known in the art and include protecting groups described in detail in organic synthesis, hydroxy protecting groups in t.w.greene and p.g.m.wuts, 3 rd edition, john wiley parent publishing company, 1999, the entire contents of which are incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4- (ethylenedithio) pentanoates, pivaloates (trimethylacetyl esters), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoates, 2, 4, 6-trimethylbenzoates, carbonates, such as methyl esters, 9-fluorenylmethyl esters, ethyl esters, 2, 2, 2-trichloroethyl esters, 2- (trimethylsilyl) ethyl esters, 2- (phenylsulfonyl) ethyl esters, vinyl esters, allyl esters, and p-nitrobenzyl esters. Examples of the silyl ethers include trimethylsilyl ether, triethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, triisopropylsilyl ether and other trialkylsilyl ethers. The alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3, 4-dimethoxybenzyl ether, trityl ether, tert-butyl ether, allyl ether and allyloxycarbonyl ether or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy) methyl ether, benzyloxymethyl ether, β - (trimethylsilyl) ethoxymethyl ether, and tetrahydropyranyl ether. Examples of arylalkyl ethers include benzyl ether, p-methoxybenzyl ether (MPM), 3, 4-dimethoxybenzyl ether, O-nitrobenzyl ether, p-halophenyl methyl ether, 2, 6-dichlorobenzyl ether, p-cyanobenzyl ether, and 2-and 4-picolyl ethers.

Amino protecting groups are well known in the art and include protecting groups described in detail in organic synthesis, hydroxyl protecting groups in t.w.greene and p.g.m.wuts, 3 rd edition, john wiley parent publishing, 1999, the entire contents of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to: aralkyl amines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include tert-Butoxycarbonyl (BOC), ethoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenethyl, trifluoroacetyl, benzoyl and the like.

Those skilled in the art will appreciate that compounds of formula I, II or III may contain one or more stereocenters and may exist as racemic or diastereomeric mixtures. It will also be appreciated by those skilled in the art that there are many methods known in the art for separating isomers to obtain stereoenriched or stereopure isomers of those compounds, including, but not limited to, HPLC, chiral HPLC, fractional crystallization of diastereomeric salts, enzymatic kinetic resolution (e.g., by fungal, bacterial or animal derived lipases or esterases) and the use of enantiomeric enrichment reagents to form covalent diastereomeric derivatives.

It will be appreciated by those skilled in the art that the various functional groups (e.g., aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles) present in the compounds of the present disclosure can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. "organic chemistry high horse, 5 th edition, editor: smith, m.b. and March, j., john willi parent-child publishing company, new york: 2001, the entire contents of which are incorporated herein by reference. The interconversion may require one or more of the foregoing techniques, and certain methods for synthesizing the compounds of the present disclosure are described in the examples below.

In some embodiments, the present disclosure provides compounds useful for the preparation of ARM. In some embodiments, the present disclosure provides compounds suitable for use in the construction of ARM molecules via cycloaddition reactions (e.g., click chemistry or variants thereof).

In some embodiments, the present disclosure provides a compound having the structure of formula IV:

or a salt thereof, wherein

ABT is an antibody binding moiety;

l is a linker moiety;

R^dIs or includes a reactive group;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Each R is independently-H, or optionally substituted selected fromGroup (b): c_1-30An aliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_1-30A heteroaliphatic group; c_6-30An aryl group; c_6-30An arylaliphatic group; c having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon_6-30An aryl heteroaliphatic group; a 5-to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and a 3-to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

Optionally and independently, two R groups together form a covalent bond, or:

As appreciated by those skilled in the art and demonstrated herein, a variety of reactive groups can be utilized in accordance with the present disclosure. For example, in some embodiments, R^dis-L^a-R', wherein R^dcomprising-C ≡ C-or-N₃(ii) a Such R^dIt is especially suitable for click chemistry reaction.

In some embodiments, the present disclosure provides a compound of formula IV-a:

or a salt thereof, wherein each variable is independently as described in the disclosure.

In some embodiments, the present disclosure provides a compound of formula IV-b:

R^c-(Xaa)z-L-R^d，

IV-b

In some embodiments, the present disclosure provides a compound of formula IV-c:

In some embodiments, the present disclosure provides a compound of formula IV-d:

In some embodiments, the present disclosure provides a compound of formula V:

In some embodiments of the present invention, the,

as described herein

In some embodiments, the target binding moiety binds to CD 38.

In some embodiments, the present disclosure provides a method comprising:

a) providing a first compound comprising a target binding moiety as described herein and a first reactive group;

b) providing a second compound comprising an antibody binding moiety as described herein and a second reactive group; and

c) reacting the first reactive group with the second reactive group to covalently link the target binding moiety to the antibody binding moiety.

In some embodiments, the first compound is a compound of formula IV, IV-a, IV-b, IV-c, or IV-d, or a salt thereof. In some embodiments, the second compound is a compound of formula V or a salt thereof.

In some embodiments, the present disclosure provides a method of preparing a compound, comprising the steps of:

providing a first compound having formula IV, IV-a, IV-b, IV-c, or IV-d, or a salt thereof, wherein the compound comprises a first reactive moiety;

providing a second compound having formula V or a salt thereof comprising a second reactive moiety; and

reacting the first compound with the second compound, wherein the first reactive moiety reacts with the second reactive moiety to link the first compound and the second compound.

Various reactive moieties and reactions can be utilized in accordance with the present disclosure. For example, in some embodiments, the reaction is an amidation reaction, wherein the first reactive moiety (e.g., R)^d) And a second reactive moiety (e.g., R)^d) Is or includes an activated carboxylic acid (e.g., is or includes

) And the other is or includes an amino group.

Reacting the first compound with the second compound, wherein the first reactive moiety reacts with the second reactive moiety via a cycloaddition reaction.

A number of cycloaddition reactions may be utilized in accordance with the present disclosure. In some embodiments, the cycloaddition reaction is [4+2 ]]And (4) reacting. In some embodiments, the cycloaddition reaction is [3+2 ]]And (4) reacting. In some embodiments, [3+2 ]]The reaction is a click chemistry reaction. In some embodiments, the first reactive moiety is-C ≡ C-and the second reactive moiety is-N₃. In some embodiments, the first reactive moiety is-N₃And the second reactive moiety is-C ≡ C-.

In some embodiments, provided techniques (e.g., compounds, agents, etc.) are or include peptide moieties. Those skilled in the art will appreciate that variable peptide synthesis techniques are readily available and can be utilized in accordance with the present disclosure.

Various techniques are available and can be used to assess provided techniques, such as the properties and/or activities of provided compounds (e.g., CD38 binding, immune activity recruitment, ADCC, etc.), in accordance with the present disclosure. Certain useful techniques are described in the examples.

5. Use, formulation and application

Pharmaceutically acceptable compositions

According to another embodiment, the present disclosure provides a composition comprising a compound described herein, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., ARM) and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure (e.g., ARM) and a pharmaceutically acceptable carrier. In some embodiments, the amount of the compound in the composition is such that it is effective to selectively direct the antibody to a target, such as a diseased cell (e.g., a cancer cell), and/or to induce an antibody-directed activity, such as cell-mediated immunity, e.g., cytotoxicity. In certain embodiments, the amount of the compound in the composition is such that it is effective to selectively direct the antibody to cancer cells expressing CD38 in a biological sample or in a subject (e.g., a cancer patient) and induce antibody-directed activity, such as cell-mediated cytotoxicity. In certain embodiments, the compositions are formulated for administration to a patient in need of such compositions. In some embodiments, the composition is formulated for oral administration to a patient.

In some embodiments, a pharmaceutically acceptable carrier, adjuvant, or vehicle is a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles may include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

In some embodiments, a pharmaceutically acceptable derivative is a non-toxic salt, ester, salt of an ester, or other derivative of a compound that is capable of providing, directly or indirectly, the compound or an active metabolite or residue thereof upon administration to a recipient.

The compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. In some embodiments, parenteral administration comprises subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions can be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

In some embodiments, mild fixed oils, including synthetic mono-or diglycerides, may be employed. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils (e.g., olive oil or castor oil, especially in their polyoxyethylated versions). These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tween, Span and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable composition may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

In some embodiments, the pharmaceutically acceptable composition may be administered in the form of suppositories for rectal administration. In some embodiments, these suppositories may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

In some embodiments, the pharmaceutically acceptable composition may also be administered topically, particularly when the target of treatment comprises an area or organ readily accessible by topical administration, including diseases of the eye, skin, or lower intestinal tract. Topical formulations suitable for each of these areas or organs are readily prepared.

Topical administration to the lower intestinal tract may be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches may also be used.

For topical administration, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable composition may be formulated as a micronized suspension or preferably as a solution in pH adjusted isotonic sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

The pharmaceutically acceptable composition may also be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is not administered with food. In other embodiments, the pharmaceutically acceptable composition is administered with food.

The amount of compound that can be combined with the carrier material to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. In some embodiments, the provided compositions are formulated such that a patient receiving these compositions can be administered a dose of between 0.01 to 100mg per kg body weight per day of the inhibitor.

It will also be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in a composition will also depend on the particular compound in the composition.

Use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally useful for selectively directing antibodies to a target, in particular a target that expresses or includes CD38, such as a diseased cell (e.g., a cancer cell), and/or for inducing antibody-directed activities, such as a cell-mediated immune response (e.g., cytotoxicity).

In some embodiments, the present disclosure provides methods of recruiting an antibody (e.g., an endogenous antibody) to a target, comprising contacting the target with a provided agent, compound, or composition. In some embodiments, the recruited antibodies comprise one or more endogenous antibodies. In some embodiments, the recruited antibody is specific for one or more antigens. In some embodiments, the recruited antibody is specific for one or more peptide antigens or proteins. In some embodiments, the recruited antibody is heterogeneous in that it is not an antibody to the same antigen or protein.

In some embodiments, the present disclosure provides methods of recruiting immune cells to a target, comprising contacting the target with a provided agent, compound, or composition.

In some embodiments, the present disclosure provides methods for triggering, generating, promoting, and/or enhancing one or more immune system activities against a target comprising contacting the target with a provided agent, compound, or composition. In some embodiments, the immune system activity is or comprises ADCC. In some embodiments, the immune system activity is or comprises ADCP. In some embodiments, the immune system activity is or includes both ADCC and ADCP. In some embodiments, the immune system activity is or comprises Complement Dependent Cytotoxicity (CDC). In some embodiments, the immune system activity is or comprises ADCVI.

In some embodiments, the target is a cancer cell. In some embodiments, the target is a cancer cell in the subject. In some embodiments, the provided methods comprise administering the provided agents, compounds, or compositions to a subject.

In some embodiments, provided agents and compounds form complexes with antibodies and Fc receptors on target cells when contacted with their targets. In some embodiments, the present disclosure provides a composite comprising:

A medicament, comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

the optional presence of a linker moiety or moieties,

an Fc region, and

an Fc receptor.

In some embodiments, the antibody binding moiety is a universal antibody binding moiety. In some embodiments, the target binding moiety may bind to CD 38.

In some embodiments, the present disclosure provides a composite comprising two or more composites, each independently comprising:

a medicament, comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

the optional presence of a linker moiety or moieties,

an Fc region, and

an Fc receptor for a protein having a high Fc activity,

wherein the Fc region of the complex is that of an antibody and/or fragment thereof directed against a different antigen or protein.

In some embodiments, the Fc region of the complex is an Fc region of an antibody and/or fragment thereof directed to a different protein. In some embodiments, the one or more Fc regions are Fc regions of endogenous antibodies and/or fragments thereof.

In some embodiments, the present disclosure provides a method of treating one or more disorders, diseases, and/or conditions, wherein the disorder, disease, or condition is cancer.

In some embodiments, "neoplasia" or "cancer" is or includes the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cell proliferation, is often faster than normal tissue, and continues to grow after cessation of the stimulus that elicits new growth. Malignant neoplasms exhibit a partial or complete lack of structural organization and function coordinated with normal tissue and most invasive surrounding tissues, metastasize to several sites, and may recur after attempted removal and cause patient death unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and encompasses or encompasses pathological processes associated with malignant hematopoiesis, ascites, and solid tumors. Representative cancers include, for example, prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain/CNS cancer, head and neck cancer, throat cancer, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral/pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, and lymphoma, among others, that can be treated by one or more compounds according to the present disclosure. Furthermore, the provided techniques (e.g., compounds, compositions, methods, etc.) are particularly useful for preventing and/or treating cancer.

Furthermore, the present disclosure provides the use of a compound according to the definitions herein or a pharmaceutically acceptable salt or hydrate or solvate thereof in the manufacture of a medicament for the treatment of a proliferative disease.

In some embodiments, the present disclosure provides techniques, e.g., agents, compounds (e.g., ARM), compositions, methods, etc., that are particularly useful for treating CD 38-associated cancers. In some embodiments, the provided techniques are particularly useful for treating cancers that express or include CD38 by cancer cells.

Combination therapy

In some embodiments, the provided techniques are administered with one or more additional therapeutic agents and/or techniques (e.g., for cancer, one or more of additional therapeutic agents, surgery, radiotherapy, etc.). In some embodiments, additional therapeutic agents and/or techniques suitable for combination are those that have been used to treat the condition, disorder or disease. In certain embodiments, a provided compound (e.g., ARM) or composition thereof is administered in combination with another therapeutic agent.

Examples of agents for combination include (but are not limited to): for the treatment of Alzheimer's Disease, e.g. Alzheimer's Disease

And

for the treatment of HIV, such as ritonavir (ritonavir); for the treatment of Parkinson's Disease, such as L-DOPA/carbidopa (carbidopa), entacapone (entacapone), ropinirole (roprole), pramipexole (pramipexole), bromocriptine (bromocriptine), pergolide (pergolide), trihexyphenidyl (trihexyphenyl) and amantadine; agents for the treatment of Multiple Sclerosis (MS), e.g. interferon beta (e.g. interferon beta)

And

)、

and mitoxantrone (mitoxantrone); for treatment of asthma, e.g. albuterol and

agents for treating schizophrenia, such as repulper (zyprexa), risperidone (risperdal), selazen (seroquel) and haloperidol (haloperidol); anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus (tacrolimus), rapamycin (rapamycin), mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole (riluzole), and antiparkinson agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders, such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3a4 inhibitors (e.g., ketenozole and ritonavir); and agents for treating immunodeficiency disorders, such as gamma globulin.

In certain embodiments, the provided compounds or compositions thereof are used in combination with a monoclonal antibody or siRNA therapeutic.

The additional agents can be administered separately from the provided compounds or compositions. Alternatively, the additional agent may be part of a single dosage form, mixed in a single composition with the provided compound. If administered as part of a multiple dosing regimen, the active agents may be administered simultaneously, sequentially or separated from each other by a period of time (typically within five hours of each other).

Combination therapy may include the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the combination may be administered simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

In some embodiments, the amount of additional therapeutic agent does not exceed the amount that would be administered when the additional therapeutic agent is not combined with a compound or composition provided herein.

In one embodiment, the present disclosure provides a composition comprising a compound of formula I, II or III and one or more additional therapeutic agents. The therapeutic agent may be administered with a compound of formula I, II or III, or may be administered before or after administration of a compound of formula I, II or III. Suitable therapeutic agents are described in more detail below. In certain embodiments, a compound of formula I, II or III can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours prior to the therapeutic agent. In other embodiments, a compound of formula I, II or III can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

In some embodiments, the present disclosure provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example: an acetamidophenol; nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin (aspirin)) Ibuprofen (ibuprofen), naproxen (naproxen), etodolac (etodolac)

And celecoxib (celecoxib); colchicine (colchicine)

Corticosteroids such as prednisone (prednisone), prednisolone (prednisone), methylprednisolone, hydrocortisone (hydrocortisone), and the like; probenecid (probenecid); allopurinol (allopurinol); febuxostat (febuxostat)

Sulfasalazine

Antimalarial drugs, e.g. hydroxychloroquine

And chloroquine

Methotrexate (methotrexate)

Gold salts, e.g. gold thioglucoside

Gold thiomalate

And auranofin (auranofin)

D-penicillamine (A)

Or

) (ii) a Azathioprine

Cyclophosphamide

Chlorambucil

Ciclosporin

Leflunomide (leflunomide)

And "anti-TNF" agents, such as etanercept (etanercept)

Infliximab (infliximab)

Golimumab (golimumab)

Cetuzumab ozolomide (certolizumab pegol)

And adalimumab (adalimumab)

"anti-IL-1" agents, e.g. anakinra

Heirancicept (rilonacept)

Kana monoclonal antibody (canakinumab)

anti-Jak inhibitors, such as tofacitinib; antibodies, e.g. rituximab (rituximab)

"anti-T cell" agents, e.g. acappe (abatacept)

"anti-IL-6" agents, e.g. tositumumab (tocilizumab)

Diclofenac (diclofenac); cortisone; hyaluronic acid (A)

Or

) (ii) a Monoclonal antibodies, such as, for example, tanizumab; anticoagulants, e.g. heparin (A), (B)

Or

) And warfarin (warfarin)

Antidiarrheals, e.g. diphenoxylate

And loperamide (loperamide)

Bile acid binders such as cholestyramine; alosetron (alosetron)

Lubiprostone(1ubiprostone)

Laxatives, e.g. magnesium milk, polyethylene glycol

And

anticholinergic or antispasmodic agents, e.g. bicyclic amines

Beta-2 agonists, e.g. salbutamol(s) ((R))

HFA、

HFA), levalbuterol

Ocinalin (metaprotenol)

Pibuterol acetate (pirbuterol acetate)

Terbutaline sulfate (terbutaline sulfate)

Salmeterol xinafoate (salmeterol)

And formoterol (formoterol)

Anticholinergic agents, for example ipratropium bromide

And tiotropium (tiotropium)

Inhaled corticosteroids, such as beclomethasone dipropionate (diproprionate) (Beclomethione)

And

) Triamcinolone acetonide (triamcinolone acetonide)

Mometasone (mometasone)

Budesonide (budesonide)

And flunisolide (flunisolide)

Cromolyn sodium salt

Methylxanthines, e.g. theophylline

And aminophylline; IgE antibodies, e.g. omalizumab

Nucleoside reverse transcriptase inhibitors, e.g. zidovudine(s) ((R))zidovudine)

Abacavir (abacavir)

Abacavir/lamivudine (lamivudine)

Abacavir/lamivudine/zidovudine

Didanosine (didanosine)

Emtricitabine (emtricitabine)

Lamivudine

Lamivudine/zidovudine

Stavudine (stavudine)

And zalcitabine (zalcitabine)

Non-nucleoside reverse transcriptase inhibitors, e.g. delavirdine

Efavirenz (efavirenz)

Nevirapine (nevairapine)

And etravirine (etravirine)

Nucleotide reverse transcriptase inhibitors, e.g. tenofovir (tenofovir)

Protease inhibitors, e.g. amprenavir (amprenavir)

Atazanavir (atazanavir)

Darunavir (darunavir)

Fusavir (fosamprenavir)

Indinavir (indinavir)

Lopinavir (lopinavir) and ritonavir

Nelfinavir (nelfinavir)

Ritonavir

Saquinavir (saquinavir) ((S))

Or

) And tipranavir (tipranavir)

Entry inhibitors, e.g. enfuvirtide

And maraviroc (maravroc)

Integrase inhibitors, e.g. raltegravir

Adriamycin (doxorubicin)

Vincristine (vincristine)

Bortezomib (bortezomib)

And dexamethasone (dexamethasone)

With lenalidomide

A combination of (1); or any combination thereof.

In some embodiments, the present disclosure provides a method of treating gout comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from: nonsteroidal anti-inflammatory drugs (NSAIDS), e.g. aspirin, ibuprofen, naproxen, etodolac

And celecoxib; colchicine

Cortex (cortex)Steroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like; probenecid; allopurinol; and febuxostat

In some embodiments, the present disclosure provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: nonsteroidal anti-inflammatory drugs (NSAIDS), e.g. aspirin, ibuprofen, naproxen, etodolac

And celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like; sulfasalazine

Antimalarial drugs, e.g. hydroxychloroquine

And chloroquine

Methotrexate (MTX)

Gold salts, e.g. gold thioglucoside

Gold thiomalate

And auranofin

D-penicillamine (A)

Or

) (ii) a Azathioprine

Cyclophosphamide

Chlorambucil

Ciclosporin

Leflunomide

And "anti-TNF" agents, e.g. etanercept

Infliximab

Gollimumab

Cytuzumab ozogamicin

And adalimumab

"anti-IL-1" agents, e.g. anakinra

And linaglicept

Antibodies, e.g. rituximab

"anti-T cell" agents, e.g. Albapup

And "anti-IL-6" agents, e.g. tositumumab

In some embodiments, the present disclosure provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from: an acetamidophenol; nonsteroidal anti-inflammatory drugs (NSAIDS), e.g. aspirin, ibuprofen, naproxen, etodolac

And celecoxib; diclofenac acid; cortisone; hyaluronic acid (A)

Or

) (ii) a And monoclonal antibodies, such as tanlizumab.

In some embodiments, the present disclosure provides a method of treating lupus, comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from: an acetamidophenol; nonsteroidal anti-inflammatory drugs (NSAIDS), e.g. aspirin, ibuprofen, naproxen, etodolac

And celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like; antimalarial drugs, e.g. hydroxychloroquine

And chloroquine

Cyclophosphamide

Methotrexate (MTX)

Azathioprine

And anticoagulants, e.g. heparin (C)

Or

) And warfarin

In some embodiments, the present disclosure provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: meishalaming (mesalamine)

Sulfasalazine

Antidiarrheals, e.g. diphenoxylate

And loperamide

Bile acid binders such as cholestyramine; alosetron

Lubiprostone

Laxatives, e.g. magnesium milk, polyethylene glycol

And

and anticholinergic or antispasmodic agents, e.g. bicyclic amines

anti-TNF therapy; a steroid; and antibiotics, such as metronidazole (Flagyl) or ciprofloxacin (ciprofloxacin).

In some embodiments, the present disclosure provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of:

beta-2 agonists, e.g. salbutamol(s) ((R))

HFA、

HFA), levalbuterol

Ocinalin

Pirbuterol acetate

Terbutaline sulfate

Salmeterol xinafoate

And formoterol

Anticholinergic agents, e.g. ipratropium bromide

And tiotropium

Inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate: (

And

) Triamcinolone acetonide

Mometasone

Budesonide

Fluniprole

And

cromolyn sodium salt

Methylxanthines, e.g. theophylline

And aminophylline; and IgE antibodies, e.g. OlympicMazuki single antibody

In some embodiments, the present disclosure provides a method of treating COPD comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from: beta-2 agonists, e.g. salbutamol(s) ((R))

HFA、

HFA), levalbuterol

Ocinalin

Pirbuterol acetate

Terbutaline sulfate

Salmeterol xinafoate

And formoterol

Anticholinergic agents, e.g. ipratropium bromide

And tiotropium

Methylxanthines, e.g. theophylline

And aminophylline; inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate: (

And

) Triamcinolone acetonide

Mometasone

Budesonide

Fluniprole

And

in some embodiments, the present disclosure provides a method of treating HIV comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: nucleoside reverse transcriptase inhibitors, e.g. zidovudine

Abacavir

Abacavir/lamivudine

Abacavir/lamivudine/zidovudine

Defenoxin

Emtricitabine

Lamivudine

Lamivudine/zidovudine

Stavudine

And zalcitabine

Non-nucleoside reverse transcriptase inhibitors, e.g. delavirdine

Efavirenz

Nevirapine

And etravirine

Nucleotide reverse transcriptase inhibitors, e.g. tenofovir

Protease inhibitors, e.g. amprenavir

Atazanavir

Darunavir

Fusavir

Indinavir

Lopinavir and ritonavir

Nelfinavir

Ritonavir

Saquinavir (a)

Or

) And tipranavir

Entry inhibitors, e.g. Enfuvirtide

And maraviroc

Integrase inhibitors, e.g. latiravir

And combinations thereof.

In some embodiments, the present disclosure provides a method of treating cancer comprising administering to a subject in need thereof a compound of formula I, II or III and one or more additional therapeutic agents. In some embodiments, the cancer is multiple myeloma. In some embodiments, the additional therapeutic agent is lenalidomide. In some embodiments, the additional therapeutic agent is bortezomib. In some embodiments, the additional therapeutic agent is dexamethasone. In some embodiments, the additional therapeutic agent is melphalan (melphalan). In some embodiments, the additional therapeutic agent is prednisone. In some embodiments, the combination is a combination of a provided compound (e.g., ARM) with lenalidomide or bortezomib and dexamethasone. In some embodiments, the combination is a combination of a provided compound (e.g., ARM) with bortezomib, melphalan, and prednisone.

In some embodiments, as demonstrated herein, the provided compounds (e.g., ARM) have low toxicity (e.g., less complement activation, less reduction of effector cells expressing CD38, etc.) compared to CD38 antibody therapy. In some embodiments, a provided compound or composition thereof, when administered as monotherapy or as part of a combination therapy, may be administered at higher and/or more frequent doses and/or for longer periods of time than other therapies (e.g., CD38 antibody therapy).

In some embodiments, the present disclosure provides a method of treating a hematologic malignancy comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from: rituximab

Cyclophosphamide

Adriamycin

Vincristine

Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

In some embodiments, the disclosureThere is provided a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: rituximab

Cyclophosphamide

Adriamycin

Vincristine

In some embodiments, the present disclosure provides a method of treating a hematologic malignancy comprising administering to a patient in need thereof a compound of formula I, II or III and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al, "defines the causative factor that leads to activation of hedgehog signaling in diffuse large B-cell lymphoma)" leukemia study (leuk.res.) (2012), published online on 7 months and 17 days, and incorporated herein by reference in its entirety).

In some embodiments, the present disclosure provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: rituximab

Cyclophosphamide

Adriamycin

Vincristine

Prednisone, hedgehog signaling inhibitors, and combinations thereof.

In some embodiments, the present disclosure provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from: bortezomib

And dexamethasone

Hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors and lenalidomide

Combinations of (a) and (b).

In some embodiments, the present disclosure provides a method of treating waldenstrom's macroglobulinemia: (

macrogolulinemia) comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: chlorambucil

Cyclophosphamide

Fludarabine (fludarabine)

Cladribine (cladribine)

Rituximab

Hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

In some embodiments, the present disclosure provides a method of treating alzheimer's disease comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: donepezil (donepezil)

Rivastigmine (rivastigmine)

Galantamine (galantamine)

Tacrine (tacrine)

Hemeijin (memantine)

In some embodiments, the present disclosure provides a method of treating organ transplant rejection or graft-versus-host disease comprising administering to a patient in need thereof a compound of formula I, II or III and one or more additional therapeutic agents selected from the group consisting of: steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

In some embodiments, the disclosure provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I, II or III and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, Systemic Lupus Erythematosus (SLE), vasculitis, Idiopathic Thrombocytopenic Purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, alder's thyroiditis, Graves ' disease, immunoautologous thyroiditis, sjogren's syndrome, multiple sclerosis, systemic sclerosis, neurolyme disease (lyurocortis, Guillain-barre syndrome), Guillain-barre syndrome (Guillain-barre myelitis), acute disseminated encephalomyelitis, or a BTK inhibitor, Edison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic imbalance, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, greater neuromuscular mycosis, scleroderma, and ocular clonus syndrome, Vulvodynia, hyperproliferative diseases, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion, systemic anaphylaxis, allergy (e.g., to plant pollen, latex, drugs, food, insect poison, animal hair, animal dander, dust mite or cockroach allergy), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, Enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, allergic purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia (pneumoconiis), pneumonia (pneumoconia), polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, eustachyositis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B cell proliferative disorders, such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, Acute lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, intranodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases, including, but not limited to, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), behcet's disease, sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer metastasis, thromboembolic disorders, (e.g., myocardial infarction, angina, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortic coronary bypass, restenosis after aortic coronary bypass, stroke, transient ischemia, peripheral arterial occlusion, pulmonary embolism, deep vein thrombosis), inflammatory pelvic conditions, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, Cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Huggelian's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic conditions, Goodpasture's syndrome, atherosclerosis, Edison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, inflammatory disease, chronic idiopathic thrombocytopenic purpura, Crohn's disease, inflammatory bowel disease, inflammatory, Waldenstrom's macroglobulinemia, myasthenia gravis, hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, guillain-barre syndrome, behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemic/reperfusion injury), and graves' disease.

In some embodiments, the present disclosure provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I, II or III and a PI3K inhibitor, wherein the disease is selected from the group consisting of cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disease, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), a liver disease, a pathological immune condition including T cell activation, a cardiovascular disorder, and a CNS disorder.

In some embodiments, the present disclosure provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I, II or III and a PI3K inhibitor, wherein the disease is selected from a benign or malignant tumor, a carcinoma or solid tumor of the brain, kidney (e.g., Renal Cell Carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, throat, skin, bone, or thyroid, a sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or gastrointestinal cancer, particularly a colon cancer or colorectal adenoma, or a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, a, Adenocarcinoma, keratoacanthoma, epidermoid tumor, large cell carcinoma, non-small cell lung carcinoma, lymphoma, (including, for example, non-hodgkin's lymphoma (NHL) and hodgkin's lymphoma (also known as hodgkin's disease or hodgkin's disease)), breast cancer, follicular cancer, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, diseases including Cowden syndrome (Cowden syndrome), lehmeter-dukes disease (lhemitte-Dudos disease), and Bannayan-zonner syndrome (Bannayan-Zonana syndrome), or diseases in which the PI3K/PKB pathway is abnormally activated; asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection; acute Lung Injury (ALI), adult/Acute Respiratory Distress Syndrome (ARDS), chronic obstructive pulmonary, respiratory or pulmonary disease (COPD, COAD or COLD), including chronic bronchitis or asthma, emphysema associated therewith; and exacerbation of airway hyperreactivity following other drug therapies, particularly other inhaled drug therapies; bronchitis of any type or origin, including, but not limited to, acute, arachis, catarrhal (catarrhal), croupus (croupus), chronic or tuberculous bronchitis; pneumoconiosis (inflammatory, commonly occupational, lung disease, often accompanied by respiratory obstruction (whether chronic or acute), and caused by repeated inhalation of dust) of any type or origin, including, for example, aluminosis, charcoal-dust disease, asbestosis, lithosis, eyelash exfoliation, ferrosis, silicosis, tobacco-dust disease, and cotton-dust disease; loffler's syndrome; eosinophilia, pneumonia, parasitic (especially multicellular animal) infections (including tropical eosinophilia); bronchopulmonary aspergillosis; polyarteritis nodosa (including Churg-Strauss syndrome)); eosinophilic granuloma and eosinophil-related disorders affecting the respiratory tract resulting from drug response; psoriasis; contact dermatitis; atopic dermatitis; alopecia areata; erythema multiforme; dermatitis herpetiformis; scleroderma; leukoderma; hypersensitivity vasculitis; urticaria; bullous pemphigoid; lupus erythematosus; pemphigus; acquired epidermolysis bullosa; conjunctivitis; dry eye syndrome; and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases in which autoimmune reactions are involved or have an autoimmune component or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia); systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; wegener's granuloma; dermatomyositis; chronic active hepatitis; myasthenia gravis; Stefin-Johnson syndrome (Steven-Johnson syndrome); idiopathic sprue; autoimmune inflammatory bowel disease (e.g., ulcerative colitis and crohn's disease); endocrine ocular disorders; gray's disease; sarcoidosis; alveolitis; chronic allergic pneumonia; multiple sclerosis; primary biliary cirrhosis, uveitis (anterior and posterior), dry eye and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minor changes in nephropathy, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure; alzheimer's disease; parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; and cerebral ischemia; and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity or hypoxia.

The compounds and compositions of the present disclosure can be administered using any amount and any route of administration effective to treat or reduce the severity of cancer or a proliferative disorder. The exact amount required may vary from subject to subject, depending on the species, age and general condition of the subject, severity, particular agent, mode of administration, and the like. In some embodiments, the compounds are formulated in unit dosage forms that are easy to administer and are uniform in dosage. In some embodiments, a unit dosage form refers to a physically discrete unit of medicament suitable for the patient to be treated. It will be understood, however, that the total daily amount of the compounds and compositions will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism may depend upon a variety of factors, including the condition, disorder and disease being treated and its severity; the activity and/or characteristics of the particular compound used; the particular composition used; the age, weight, general health, sex, and diet of the subject; time of administration, route of administration, and/or rate of excretion of the particular compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors well known in the medical arts. In some embodiments, the patient is an animal, preferably a mammal, and most preferably a human.

Pharmaceutically acceptable compositions may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, as an oral or nasal spray, and the like, depending on the severity of the infection being treated. In certain embodiments, the compounds may be administered orally or parenterally at dosage levels of about 0.01mg to about 50mg, and in some embodiments, about 1mg to about 25mg, per kilogram of subject body weight per day, one or more times per day, to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be employed are water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporation of sterilizing agents, in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the present disclosure, it is often desirable to slow the absorption of the subcutaneously or intramuscularly injected compounds. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues.

In some embodiments, compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the compound with a suitable non-irritating excipient or carrier, for example cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with: at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Tablets, dragees, capsules, pills and granules of solid dosage forms can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. It may optionally contain opacifying agents and may also have a composition such that it releases only or preferentially one or more active ingredients, optionally in a certain portion of the intestinal tract, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more excipients as mentioned above. Tablets, dragees, capsules, pills and granules of solid dosage forms can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). Such dosage forms may also include, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. It may optionally contain opacifying agents and may also have a composition such that it releases only or preferentially one or more active ingredients, optionally in a certain portion of the intestinal tract, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as required. In some embodiments, the composition is an ophthalmic formulation, ear drops, or eye drops. In addition, the present disclosure encompasses the use of transdermal patches, which have the added advantage of allowing controlled delivery of the compound to the body. The dosage form may be manufactured by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

In some embodiments, the present disclosure provides a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

In some embodiments, the biological sample comprises, but is not limited to, a cell culture or extract thereof; a biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Depending on the particular condition or disease to be treated, additional therapeutic agents typically administered to treat the condition may also be present in the compositions of the present disclosure. As used herein, an additional therapeutic agent normally administered for the treatment of a particular disease or condition is referred to as "appropriate for the disease or condition being treated.

Furthermore, the compounds and/or compositions of the present disclosure may be used in combination therapy, i.e., the compounds and/or compositions of the present disclosure may be administered simultaneously with, prior to, or after one or more other therapeutic agents or medical procedures, particularly for the treatment of various cancers. In some embodiments, the compounds of the present disclosure may also be advantageously used in combination with other anti-proliferative compounds. The particular combination of therapies (therapeutic agents or procedures) used in a combination regimen will take into account the compatibility of the other therapeutic agents and/or procedures required and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies used may achieve the desired effect against the same condition (e.g., the compound provided may be administered simultaneously with another anti-cancer agent), or that the therapies may achieve different effects (e.g., control of any adverse effects). In some embodiments, the therapeutic agent is a chemotherapeutic agent or an anti-proliferative compound. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormonal therapy drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer agents. In addition, the provided technology can be used with or prepared as a mixture with leukopenia (neutrophil) drugs, thrombocytopenia drugs, antiemetic drugs, and cancer pain drugs for QOL recovery in patients as cancer treatment adjuvants. In some embodiments, the therapeutic agent is an antibody. In some embodiments, the therapeutic agent is an immunomodulatory agent. In some embodiments, the immunomodulator targets a cell surface signaling molecule on an immune cell. In some embodiments, the immunomodulatory agent targets a cell surface signaling molecule on an immune cell, wherein the agent is an antagonist that blocks a co-inhibitory pathway. In some embodiments, the immune modulator is a checkpoint blockade agent. In some embodiments, the immunomodulator is an antibody that targets a cell surface signaling protein expressed by an immune cell. In some embodiments, the immunomodulatory agent is an antibody that targets a protein selected from PD-1, PD-L1, CTLA4, TIGIT, BTLA, TIM-3, LAG3, B7-H3, and B7-H4. In some embodiments, the immunomodulator is a PD-1 antibody (e.g., nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL328OA, etc.). In some embodiments, the immunomodulator is a PD-L1 antibody. In some embodiments, the immunomodulatory agent is a CTLA4 antibody (e.g., ipilimumab). In some embodiments, the immunomodulatory agent is a TIGIT antibody. In some embodiments, the immunomodulatory agent is a BTLA antibody. In some embodiments, the immunomodulator is a Tim-3 antibody. In some embodiments, the immunomodulatory agent is a LAG3 antibody. In some embodiments, the immunomodulator is a B7-H3 antibody. In some embodiments, the immunomodulator is a B7-H4 antibody. In some embodiments, the immunomodulator targets a cell surface signaling molecule on an immune cell, wherein the agent is an agonist involved in a co-stimulatory pathway. In some embodiments, such immunomodulatory agents are or include antibodies that target co-stimulatory receptors. In some embodiments, the antibody activates a T cell co-stimulatory receptor. In some embodiments, the antibody targets a member of the Tumor Necrosis Factor (TNF) receptor superfamily. In some embodiments, the antibody targets a protein selected from CD137(4-1BB), CD357(GITR, TNFRS18, AITR), CD134(OX40), and CD40 (TNFRSF 5). In some embodiments, the antibody is an anti-CD 137 antibody (e.g., ureluzumab). In some embodiments, the antibody is an anti-CD 357 antibody. In some embodiments, the antibody is an anti-CD 40 antibody. In some embodiments, the antibody is an anti-CD 134 antibody. Additional exemplary T cell co-stimulatory and co-inhibitory receptors are described in Chen L, Flies DB., the Molecular mechanisms of T cell co-stimulation and co-inhibition (Molecular mechanisms of T cell co-stimulation and co-inhibition), nature review immunology (nat. rev. immunol.)2013, 13(4), 227-42 and Yao S et al, Advances in targeting cell surface signaling molecules for immunomodulation (advancement in targeting cell surface signaling molecules for immunization modification), nature review drug discovery (nat. rev. drug discovery) 2013, 12(2), 136-40. In some embodiments, the therapeutic agent is an antibody that activates such stimulatory receptors or blocks such inhibitory receptors.

In some embodiments, the one or more additional therapeutic agents are or include tumor-specific immune cells. In some embodiments, the one or more additional therapeutic agents are or include tumor-specific T cells. In some embodiments, the one or more additional therapeutic agents is or includes Tumor Infiltrating Lymphocytes (TILs). In some embodiments, the one or more additional therapeutic agents are or comprise T cells ectopically expressing a known anti-tumor T Cell Receptor (TCR). In some embodiments, the one or more additional therapeutic agents is or includes a Chimeric Antigen Receptor (CAR) T cell. In some embodiments, provided compositions include an immune enhancing substance. Exemplary immune enhancing substances that can be used in combination with the provided compounds, compositions, and/or methods include, but are not limited to, various cytokines and tumor antigens. Cytokines that stimulate an immune response include, for example, GM-CSF, M-CSF, G-CSF, interferon- α, interferon- β, interferon- γ, IL-1, IL-2, IL-3, and IL-12, and the like. Antibodies that block inhibitory receptors and/or activate stimulatory receptors, such as, but not limited to, B7 ligand derivatives, anti-CD 3 antibodies, anti-CD 28 antibodies, and anti-CTLA-4 antibodies, are also known in the art and described herein, can improve immune responses. In some embodiments, the therapeutic agent is a small molecule for immunomodulation. In some embodiments, the therapeutic agent is a small molecule that mediates antitumor immune activity. In some embodiments, the therapeutic agent is a small molecule that targets an enzyme directly involved in immune modulation. In some embodiments, the therapeutic agent is an indoleamine 2, 3-dioxygenase (IDO) inhibitor. In some embodiments, the therapeutic agent is an IDO1 inhibitor, such as F001287, indoimod (indoximod), NLG-919, and INCB 024360. In some embodiments, the therapeutic agent is a tryptophan-2, 3 dioxygenase (TDO) inhibitor. In some embodiments, the therapeutic agent is a dual IDO/TDO inhibitor. In some embodiments, the therapeutic agent is an IDO selective inhibitor. In some embodiments, in some other embodiments, the therapeutic agent is a TDO selective inhibitor. In some embodiments, provided compositions include an IDO inhibitor and a first construct. In some embodiments, provided compositions include an IDO inhibitor, a first construct, and a second construct. It will be appreciated that the immune response to the first construct and/or the second construct may be significantly enhanced by administration of an IDO inhibitor.

In some embodiments, medical procedures that can be used in combination with the compounds, compositions, and methods of the present application include, but are not limited to, surgery, radiotherapy (gamma-irradiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes, to name a few), endocrine therapy, biological response modifiers (interferons, interleukins, and Tumor Necrosis Factor (TNF), to name a few), hyperthermia, cryotherapy, and adoptive T cell transfer (e.g., TIL therapy, transgenic TCR, CAR T cell therapy, NK cell therapy, etc.). In some embodiments, the medical procedure is surgery. In some embodiments, the medical procedure is radiotherapy.

In some embodiments, the provided techniques include provided agents (e.g., provided agents that include moieties that can bind to CD 38) and cell populations (e.g., cells of a cell-based therapy). In some embodiments, provided techniques include provided agents and effector cell populations. In some embodiments, the cell population is a manipulated cell population, e.g., that is typically engineered, activated, enriched, and/or expanded, etc. In some embodiments, the cell population is a manufactured cell population. In some embodiments, the cell population is enriched for certain types of desired cells. In some embodiments, the effector cell is an NKT cell. In some embodiments, the effector cell is a monocyte. In some embodiments, the effector cell is a macrophage. In some embodiments, the effector cell is a T cell. In some embodiments, the effector cell is a CAR T cell. In some embodiments, the effector cell is an NK cell, e.g., a cytokine-induced memory-like NK cell, a CAR-NK cell, an engineered NK cell that expresses or does not express certain proteins (e.g., receptors), and can be from a variety of sources. As will be appreciated by those skilled in the art, suitable immune cells (e.g., NK cells) can be derived from a variety of sources and/or engineered in a variety of ways. For example, in some embodiments, the NK cells are memory-like NK cells. In some embodiments, the NK cells are cytokine-induced memory-like NK cells. In some embodiments, the NK cells are derived from stem cells. In some embodiments, the NK cells are derived from an iPSC cell line. In some embodiments, the NK cells are derived from a clonal master iPSC cell line. In some embodiments, the NK cells are engineered to express certain receptors, such as the high affinity, optionally non-cleavable, CD16 receptor. In some embodiments, the NK cell is engineered to express a Chimeric Antigen Receptor (CAR), e.g., in some embodiments, the NK cell can be engineered to express an anti-CD 19 CAR. In some embodiments, the NK cell is a CAR-NK cell. In some embodiments, the NK cell is engineered to express a cytokine receptor. In some embodiments, the NK cells comprise IL-15 receptorbody that enhances persistence and expansion without the need for co-administration of cytokine loads. In some embodiments, the NK cells are engineered to prevent expression of certain cellular proteins (e.g., certain cell surface proteins). In some embodiments, the NK cell is engineered to prevent expression of CD 38. In some embodiments, the NK cells are derived from placenta. In some embodiments, the NK cell is a donor NK cell. In some embodiments, the NK cells are haploid concordant donor NK cells. In some embodiments, the NK cells are mismatched donor NK cells. In some embodiments, the NK cell is a related donor NK cell, e.g., a mismatched related donor NK cell. In some embodiments, the NK cell is an unrelated donor NK cell. In some embodiments, the NK cells are derived from a subject, e.g., a patient. In some embodiments, the provided techniques include a innate cell engager, such as one that binds to innate cells (e.g., NK cells and macrophages) while binding to specific tumor cells. In some embodiments, the NK cells are derived from cord blood stem cells and progenitor cells. In some embodiments, the NK cell is derived from the modulation of a signaling pathway (e.g., Notch signaling pathway). In some embodiments, the nanoparticles are utilized to improve and/or maintain the growth of NK cells. In some embodiments, as described herein, the NK cells are produced ex vivo. In some embodiments, NK cells can be cryopreserved and stored as a ready-made cell therapy in multiple doses. Examples of some such technologies include those utilized by fat Therapeutics, natkwest, cellularity, green cross pharmaceutical (GC Pharma), sorento Therapeutics, Inc, affimted/MD Anderson Cancer Center (MD Anderson Cancer Center), gamda Cell co. Those skilled in the art will appreciate that where such techniques can optionally be utilized, antibodies and/or CARs to particular antigens utilized in certain such techniques may not be required in provided techniques including ARM as described herein. In some embodiments, the provided agent, cell (e.g., effector cell), and optionally immunoglobulin (e.g., IgG (e.g., intravenous immunoglobulin)) are administered to a subject such that the subject can be exposed to the provided agent and cell. In some embodiments, the provided agent and the cell (e.g., effector cell) are administered simultaneously, either in a single composition (e.g., a composition comprising the provided agent, the cell (e.g., effector cell), and optionally the immunoglobulin), or separately; in some embodiments, the provided agents are administered before or after the cells (e.g., effector cells). In some embodiments, the present disclosure provides methods for treating various conditions, disorders or diseases (e.g., various cancers) comprising administering the provided agents and cells to a subject suffering from or susceptible to the condition, disorder or disease. In some embodiments, the cells (e.g., effector cells) are stored (e.g., cryopreserved) with the provided agent (e.g., ARM agent). In some embodiments, it is thawed and administered as a single composition. In some embodiments, one or more doses of cells (e.g., effector cells) are administered followed by a dose of the provided agent (e.g., an ARM agent). In some embodiments, the dose of agent provided is a single systemic dose. In some embodiments, multiple doses of cells (e.g., effector cells) are administered, followed by a dose (in some cases a single systemic dose) of the provided agent (e.g., an ARM agent). In some embodiments, an agent (e.g., an ARM agent) is administered (e.g., systemically, in some cases a single systemic administration), followed by one or more (in some cases multiple) doses of cells (e.g., effector cells). In some embodiments, an agent (e.g., an ARM agent) is administered (e.g., systemically, in some cases a single systemic administration), followed by one or more (in some cases multiple) each independent dose of cells (e.g., effector cells) or cells and provided agent (e.g., ARM agent), wherein the cells and provided agent can be administered in a combined composition or in separate compositions.

Further, such provided techniques may provide enhanced efficacy and/or reduced side effects.

Anti-proliferative compounds include, but are not limited to, aromatase inhibitionAn agent; an antiestrogen; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active compound; an alkylating compound; (ii) a histone deacetylase inhibitor; compounds that induce a cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; antineoplastic antimetabolites; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; a compound that targets, reduces or inhibits the activity of a protein or lipid phosphatase; a gonadorelin (gonadorelin) agonist; an antiandrogen; a methionine aminopeptidase inhibitor; a matrix metalloproteinase inhibitor; a bisphosphonate; a biological response modifier; an anti-proliferative antibody; a heparinase inhibitor; inhibitors of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; compounds for use in the treatment of hematological malignancies; a compound that targets, decreases or inhibits the activity of Flt-3; hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Comfortma Therapeutics; temozolomide (temozolomide)

Spindle kinesin inhibitors, such as SB715992 or SB743921 from glatiramer (GlaxoSmithKline), or pentamidine (pentamidine)/chlorpromazine from portentos (CombinatoRx); MEK inhibitors, such as ARRY142886 from alay biopharmaceutical (Array BioPharma), AZD6244 from astrikon (AstraZeneca), PD181461 from Pfizer, and leucovorin. As used herein, the term "aromatase inhibitor" relates to a compound that inhibits estrogen production, e.g. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane (atamestane), exemestane (exemestane), and formestane (formestane); and in particular non-steroids, in particular aminoglutethimide, roglucimide, pirglutethimide, troloxacillinTandane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is available under the trade name Aromasin^TMAnd (5) selling. Formestane is under the trade name Lentaron ^TMAnd (5) selling. Fadrozole is given the trade name Afema^TMAnd (5) selling. Anastrozole is given the trade name Arimidex^TMAnd (5) selling. Letrozole is given the trade name Femara^TMOr Femar^TMAnd (5) selling. Aminoglutethimide under the trade name Orimeten^TMAnd (5) selling. Combinations of the present disclosure that include chemotherapeutic agents that are aromatase inhibitors are particularly useful for treating hormone receptor positive tumors, such as breast tumors.

In some embodiments, the antiestrogen is a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen (tamoxifen), fulvestrant (fulvestrant), raloxifene (raloxifene), and raloxifene hydrochloride. Tamoxifen is available under the trade name Nolvadex^TMAnd (5) selling. Raynaxiphenol hydrochloride is under the trade name Evista^TMAnd (5) selling. Fulvestrant may be under the brand name Faslodex^TMAnd (4) application. Combinations of the present disclosure that include chemotherapeutic agents that are anti-estrogens are particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

In some embodiments, the antiandrogen is a substance capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex)^TM). As used herein, the term "gonadoliberin agonist" includes, but is not limited to abarelix (abarelix), goserelin (goserelin), and goserelin acetate. Goserelin may be under the trade name Zoladex ^TMAnd (4) application.

In some embodiments, topoisomerase I inhibitors include, but are not limited to, topotecan (topotecan), gimatecan (gimatecan), irinotecan (irinotecan), camptothecin (camptothecan), and its analog 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148. Irinotecan may be, for example, in its form of sale (e.g. under the trademark Camptosar)^TM) And (4) application. Topotecan is known under the trade name Hycamptin^TMAnd (5) selling.

In some embodiments, the topoisomerase II inhibitor comprises, but is not limited to, an anthracycline, such as doxorubicin (comprising a liposome formulation, such as Caelyx)^TM) Daunorubicin (daunorubicin), epirubicin (epirubicin), idarubicin (idarubicin) and nemorubicin (nemorubicin), anthraquinone mitoxantrone and losoxantrone (losoxantrone), and etoposide (etoposide) and teniposide (teniposide). Etopophos is the trade name Etopophos^TMAnd (5) selling. Teniposide is sold under the trade name VM 26-Bristol. Adriamycin is known under the trade name Acribilastin T^MOr Adriamycin^TMAnd (5) selling. Epirubicin is known under the trade name Farmorubicin^TMAnd (5) selling. Idarubicin is available under the trade name Zavedos^TMAnd (5) selling. Mitoxantrone is sold under the trade name Novantron.

In some embodiments, the microtubule active agents are microtubule stabilizing, microtubule destabilizing compounds and tubulin (microtubulin) polymerization inhibitors, including but not limited to taxanes (taxanes), such as paclitaxel (paclitaxel) and docetaxel (docetaxel); vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine (vinorelbine); dieschorlide (discodermolide); colchicine and epothilone (epothilone) and derivatives thereof. Taxol is given the trade name Taxol^TMAnd (5) selling. Docetaxel having the trade name Taxotere^TMAnd (5) selling. Vinblastine sulfate is under the trade name Vinblasttin R.P^TMAnd (5) selling. Vincristine sulfate is known under the trade name Farmistin^TMAnd (5) selling.

In some embodiments, the alkylating agent comprises, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamides are known under the trade name cyclosatins^TMAnd (5) selling. Ifosfamide is known under the trade name Holoxan^TMAnd (5) selling.

In some embodiments, the histone deacetylase inhibitor or HDAC inhibitor is a compound that inhibits histone deacetylase and has antiproliferative activity. This includes, but is not limited to suberoylanilide hydroxamic acid (SAHA).

In some embodiments, the antineoplastic antimetabolite comprisesBut are not limited to 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (e.g., pemetrexed). Capecitabine is under the trade name Xeloda^TMAnd (5) selling. Gemcitabine under the trade name Gemzar^TMAnd (5) selling.

In some embodiments, platinum compounds include, but are not limited to, carboplatin (carboplatin), cisplatin (cis-platinum), cisplatin (cissplatinum), and oxaliplatin (oxaliplatin). Carboplatin can be sold, for example, under the trademark Carboplat^TMAnd (4) application. Oxaliplatin can be sold, for example, under the trademark Eloxatin^TMAnd (4) application.

In some embodiments, protein or lipid kinase activity is targeted/reduced; or a protein or lipid phosphatase activity; or other anti-angiogenic compounds include, but are not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit the activity of Platelet Derived Growth Factor Receptor (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib (imatinib), SU101, SU6668 and GFB-111; b) a compound that targets, reduces or inhibits the activity of a Fibroblast Growth Factor Receptor (FGFR); c) a compound that targets, reduces or inhibits the activity of insulin-like growth factor receptor I (IGF-IR), for example a compound that targets, reduces or inhibits the activity of IGF-IR, in particular a compound that inhibits the kinase activity of IGF-I receptor, or an antibody that targets the extracellular domain of IGF-I receptor or its growth factor; d) a compound that targets, reduces or inhibits the activity of the Trk receptor tyrosine kinase family, or an ephrin B4 inhibitor; e) a compound that targets, reduces or inhibits the activity of the AxI receptor tyrosine kinase family; f) a compound that targets, decreases or inhibits the activity of Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of Kit/SCFR receptor tyrosine kinases, such as imatinib; h) targeting, lowering Compounds that reduce or inhibit the activity of the C-Kit receptor tyrosine kinase that is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the C-Kit receptor tyrosine kinase family, especially compounds that inhibit the C-Kit receptor, such as imatinib; i) compounds that target, decrease or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, e.g., compounds that target, decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN 107); PD 180970; AG 957; NSC 680410; PD173955 from parkievis (ParkeDavis); or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of a member of the Raf family of protein kinases c (pkc) and serine/threonine kinases, MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC families, and/or a member of the cyclin dependent kinase family (CDK), including staurosporine derivatives, such as midostaurin; examples of other compounds include UCN-01, safrog (safingol), BAY 43-9006, Bryostatin (Bryostatin)1, piperacillin (Perifosine); imofosine (llmofosine); RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY 379196; an isoquinoline compound; FTI; PD184352 or QAN697(P13K inhibitor) or AT7519(CDK inhibitor); k) compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, comprising imatinib mesylate (Gleevec) ^TM) Or tofukast (tyrphostin), such as tofukast A23/RG-50810; AG 99; tafosistin AG 213; tafosastine AG 1748; tafosastine AG 490; tafosastine B44; tafosistine B44(+) enantiomer; tafosistin AG 555; AG 494; tafosiltin AG 556, AG957 and adaphtin (adaphstin) (4- { [ (2, 5-dihydroxyphenyl) methyl]Amino } -benzoic acid adamantane esters; NSC 680410, adafostine); 1) epidermal growth factor family (EGFR) that targets, reduces or inhibits receptor tyrosine kinases₁ErbB2, ErbB3, ErbB4 in homo-or hetero-polymer formDimeric form) and mutants thereof, e.g. compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family, in particular compounds that inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4, or bind to EGF or EGF-related ligands, proteins or antibodies, CP358774, ZD 1839, ZM 105180; trastuzumab (trastuzumab) (Herceptin)^TM) Cetuximab (Erbitux)^TM) Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo- [2, 3-d ] ]A pyrimidine derivative; m) a compound that targets, reduces or inhibits the activity of the c-Met receptor, e.g., a compound that targets, reduces or inhibits the activity of c-Met, particularly a compound that inhibits the kinase activity of the c-Met receptor, or an antibody that targets the extracellular domain of c-Met or binds HGF; n) compounds that target, decrease or inhibit the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baritinib (baritinib), paritinib (pactinib), molotetinib (momelotinib), VX-509, AZD-1480, TG-101348, tofacitinib, and lucolintinib; o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib (buparlisib), pitrielixib (pictelisib), PF-4691502, BYL-719, dalutoxib (dactylisib), XL-147, XL-765, and idecoxib (idelalisib); and q) compounds that target, decrease or inhibit the signaling effect or smoothing receptor (SMO) pathway of hedgehog (Hh), including but not limited to cyclopamine, vismodegib (vismodegib), itraconazole (itraconazole), imodegi (eriodegib), and IPI-926 (saridegib).

In some embodiments, PI3K inhibitors include, but are not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110- α, p110- β, p110- γ, p110- δ, p85- α, p85- β, p55- γ, p150, p101, and p 87. Examples of PI3K inhibitors include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparxib, Pitrixib, PF-4691502, BYL-719, daluxib, XL-147, XL-765, and idexib.

In some embodiments, the BTK inhibitor comprises, but is not limited to, a compound having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

In some embodiments, SYK inhibitors include, but are not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Iselier (Excellair), PRT-062607, and fostatinib (fostamatinib).

Further examples of BTK inhibiting compounds and conditions that can be treated by the compounds in combination with the disclosed compounds can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

Further examples of SYK inhibiting compounds and conditions that may be treated by the compounds in combination with the disclosed compounds may be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

Further examples of PI3K inhibiting compounds and conditions that can be treated by the compounds in combination with the disclosed compounds can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

Other examples of JAK-inhibiting compounds and conditions that can be treated by the compounds in combination with the presently disclosed compounds can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entire contents of which are incorporated herein by reference.

Other anti-angiogenic compounds include those that have another mechanism of activity,for example compounds not related to protein or lipid kinase inhibition, such as thalidomide (Thalomid)^TM) And TNP-470.

Examples of proteasome inhibitors suitable for use in combination with the compounds of the present disclosure include, but are not limited to, bortezomib, disulfiram (disulfiram), epigallocatechin-3-gallate (EGCG), salinosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN 9708.

Compounds targeting, decreasing or inhibiting the activity of a protein or lipid phosphatase are for example inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid (okadaic acid) or derivatives thereof.

Compounds that induce a cellular differentiation process include, but are not limited to, retinoic acid, alpha-, gamma-, or delta-tocopherol, or alpha-, gamma-, or delta-tocotrienol.

In some embodiments, the cyclooxygenase inhibitor comprises, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex)^TM) Rofecoxib (Vioxx)^TM) Etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2- (2 '-chloro-6' -fluoroanilino) phenylacetic acid, lumiracoxib.

In some embodiments, bisphosphonates include, but are not limited to, itraconazole (ethidonic acid), clodronic acid (clodronic acid), tiludronic acid (tiludronic acid), pamidronic acid (pamidronic acid), alendronic acid (alendronic acid), ibandronic acid (ibandronic acid), risedronic acid (risedronic acid), and zoledronic acid (zoledronic acid). Didronic acid under the trade name Didronel^TMAnd (5) selling. Chlorophosphonic acids under the trade name Bonefos ^TMAnd (5) selling. Telophosphonic acid under the trade name Skelid^TMAnd (5) selling. Pamidronic acid is under the trade name Aredia^TMAnd (5) selling. Alendronic acid under the trade name Fosamax^TMAnd (5) selling. Ibandronic acid is given the trade name Bondranat^TMAnd (5) selling. Risedronic acid under the trade name Actonel^TMAnd (5) selling. Zomet phosphonic acid under the trade name Zomet^TMAnd (5) selling. In some embodiments, mTOR inhibitsThe agent is a compound that inhibits mammalian target of rapamycin (mTOR) and has antiproliferative activity, such as sirolimus

Everolimus (Certican)^TM) CCI-779 and ABT 578.

In some embodiments, the heparinase inhibitor is a compound that targets, reduces or inhibits the degradation of heparin sulfate. Including but not limited to PI-88. In some embodiments, the biological response modifier is a lymphokine or an interferon.

In some embodiments, inhibitors of Ras oncogenic isoforms (e.g., H-Ras, K-Ras, or N-Ras) are compounds that target, decrease, or inhibit the oncogenic activity of Ras; for example "farnesyl transferase inhibitors", for example L-744832, DK8G557 or R115777 (Zarnestra)^TM). In some embodiments, the telomerase inhibitor is a compound that targets, decreases, or inhibits telomerase activity. Compounds which target, decrease or inhibit telomerase activity are in particular compounds which inhibit the telomerase receptor, for example telomerase (telomestatin).

In some embodiments, the methionine aminopeptidase inhibitor is a compound that targets, reduces, or inhibits methionine aminopeptidase activity. Compounds that target, decrease or inhibit methionine aminopeptidase activity include, but are not limited to, benguanamide (bengamide) or derivatives thereof.

In some embodiments, the proteasome inhibitor is a compound that targets, decreases, or inhibits proteasome activity. Compounds that target, decrease or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade)^TM) And MLN 341.

In some embodiments, matrix metalloproteinase inhibitors or ("MMP" inhibitors) include, but are not limited to, collagen peptide mimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the oxamido peptidomimetic inhibitor batimastat (batimastat) and its analogs with oral bioavailability marimastat (marimastat) (BB-2516), prinomastat (prinomastat) (AG3340), metamastat (metastat) (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ 996.

In some embodiments, the compound for treating hematological malignancies comprises, but is not limited to, an FMS-like tyrosine kinase inhibitor, which is a compound that targets, decreases or inhibits the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-beta-D-arabinofuranosyl cytosine (ara-c) and busulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN 518.

In some embodiments, HSP90 inhibitors include, but are not limited to, compounds that target, decrease or inhibit the intrinsic ATPase (ATPase) activity of HSP 90; compounds that degrade, target, reduce or inhibit HSP90 client proteins (client proteins) via the ubiquitin proteasome pathway. Compounds which target, reduce or inhibit the intrinsic atpase activity of HSP90 are in particular compounds, proteins or antibodies which inhibit the atpase activity of HSP90, such as 17-allylamino, 17-dimethoxy geldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol (radicicol); and HDAC inhibitors.

In some embodiments, the anti-proliferative antibody comprises, but is not limited to, trastuzumab (Herceptin)^TM) trastuzumab-DM 1, erbitux, bevacizumab Avastin^TM) Rituximab, and methods of use

PRO64553 (anti-CD 40) and 2C4 antibodies. In some embodiments, the antibodies are intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, or antibody fragments so long as they exhibit the desired biological activity.

For the treatment of Acute Myeloid Leukemia (AML), the compounds of the present disclosure can be used in combination with standard leukemia therapies, particularly in combination with therapies used to treat AML. In particular, the compounds of the present disclosure may be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for treating AML, such as daunorubicin, Adriamycin (Adriamycin), Ara-C, VP-16, teniposide, mitoxantrone, idamycin, carboplatin, and PKC 412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog which is a 2' - α -hydroxyribose (arabinoside) derivative of deoxycytidine. Purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate (fluorabane phosphate) are also included. Compounds that target, decrease or inhibit the activity of Histone Deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include compounds disclosed in MS275, SAHA, FK228 (formerly FR901228), trichostatin a (trichostatin a) and US 6,552,065, including, but not limited to, N-hydroxy-3- [4- [ [ [2- (2-methyl-1H-indol-3-yl) -ethyl ] -amino ] methyl ] phenyl ] -2E-2-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3- [4- [ (2-hydroxyethyl) {2- (1H-indol-3-yl) ethyl ] -amino ] methyl ] phenyl ] -2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. In some embodiments, the somatostatin receptor antagonist is a compound that targets, treats, or inhibits a somatostatin receptor, such as octreotide (octreotide) and SOM 230. In some embodiments, the tumor cell destruction method is a method such as ionizing radiation. In some embodiments, the ionizing radiation is ionizing radiation that is carried out in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiotherapy and is known in the art. See Hellman, Principles of Cancer radiotherapy (Cancer), Oncology Principles and practices (Principles and Practice of Oncology), Devita et al, 4 th edition, Vol.1, p.248-275 (1993).

EDG binding agents and ribonucleotide reductase inhibitors are also included. In some embodiments, EDG binding agents are a class of immunosuppressive agents that modulate lymphocyte recirculation, such as FTY 720. In some embodiments, the ribonucleotide reductase inhibitor is a pyrimidine or purine nucleoside analog, including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and/or pentostatin (pentostatin). Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1, 3-dione derivatives.

Those compounds, proteins or monoclonal antibodies which also comprise VEGF, inter alia, such as 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof, 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine succinate; angiostatin^TM；Endostatin^TM(ii) a Anthranilic acid amides; ZD 4190; ZD 6474; SU 5416; SU 6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as the marijuana supply (Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2IgGI antibodies, Amphibin (Angiozyme) (RPI 4610) and bevacizumab (Avastin) ^TM)。

In some embodiments, photodynamic therapy is a therapy for treating or preventing cancer using certain chemicals known as photoactive compounds. Examples of photodynamic therapy include treatment with, for example, Visudyne^TMAnd porfimer sodium.

In some embodiments, the angiogenesis inhibiting steroid is a compound that blocks or inhibits angiogenesis, such as anecortave (anecortave), triamcinolone (triamcinolone), hydrocortisone, 11-alpha-epihydrocortisone, deoxycorticosterol (cortixolone), 17 alpha-hydroxyprogesterone, corticosterone (corticosterone), deoxycorticosterone (desoxycorticosterone), testosterone, estrone, and dexamethasone.

In some embodiments, the corticosteroid-containing implant is a compound such as fluocinolone (fluocinolone) and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, such as lymphokines or interferons; an antisense oligonucleotide or oligonucleotide derivative; shRNA or siRNA; or hybrid compounds or compounds with other or unknown mechanisms of action.

In some embodiments, the compounds of the present disclosure are also useful as adjunctive therapeutic compounds for use in combination with other drug substances, e.g., anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly for the treatment of obstructive or inflammatory tracheal diseases such as those mentioned above, e.g., as potentiators of therapeutic activity of the drug or as methods of reducing required dosages or potential side effects of the drug. In some embodiments, the disclosed compounds may be mixed with other drug substances in the form of a fixed pharmaceutical composition or they may be administered separately, before, simultaneously or after the other drug substances. Accordingly, the present disclosure provides a combination of a provided compound as described above and an anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substance, the pharmaceutical composition of the provided compound and the drug substance being the same or different.

Suitable anti-inflammatory agents include steroids, especially glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; a non-steroidal glucocorticoid receptor agonist; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast (montelukast) and zafirlukast (zafirlukast); PDE4 inhibitors, such as cilomilast (cilomilast) (II)

Glassware Sc), Roflumilast (Roflumilast) (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Arofylline) (Almirall Prodesfara), PD189659/PD168787 (Pake-Davis), AWD-12-281 (Asta Medica)), CDC-801 (Seill gene), SeICID (TM) CC-10004 (Seal gene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (synergic and cozeb), Rofluvilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer Prodesr), PD 1899/PD 168787 (Pax-Dai), and K-4490 (Cox and Nippon-K)Industry (Kyowa Hakko Kogyo)); a2a agonist; an A2b antagonist; and β -2 adrenoceptor agonists such as salbutamol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol (procaterol) and especially formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226(Chiesi) and glycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophenol fumarate, clemastine fumarate, promethazine, loratadine (loratidine), desloratadine (desloratidine), diphenhydramine (diphenhydramine) and phenafenadine hydrochloride (fexofenadine hydrochloride), avastine (activivastine), astemizole (astemizole), azelastine (azelastine), ebastine (ebastine), epinastine (epinasstine), mizolastine (mizolastine) and terfenadine (tefenadine).

Other suitable combinations of compounds with anti-inflammatory agents are antagonists of chemokine receptors, for example CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists, such as the pioneer and bayan antagonists SC-351125, SCH-55700 and SCH-D, and Wutian antagonists, such as those combinations of N- [ [4- [ [ [6, 7-dihydro-2- (4-methylphenyl) -5H-benzo-cyclohept-8-yl ] carbonyl ] amino ] phenyl ] -methyl ] tetrahydro-N, N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

The structures of active compounds identified by code number, common name or trade name can be obtained from The "Merck Index" of The current edition of The standard schema or from databases, such as The International patent (Patents) (e.g. The IMS World Publications).

The disclosed compounds may also be used in combination with known therapeutic methods, such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiotherapy.

The disclosed compounds may be administered alone or in combination with one or more other therapeutic compounds, with possible combination therapies employing fixed combinations or staggered or independent of each other to provide administration of the disclosed compounds and one or more other therapeutic compounds, or a combination of a fixed combination and one or more other therapeutic compounds. The disclosed compounds may be administered additionally or alternatively, especially in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these, for the treatment of tumors. In the case of other treatment strategies, long-term therapy and adjuvant therapy are likewise possible, as described above. Other possible treatments are therapies that maintain the patient's state after tumor regression or even chemopreventive therapies (e.g. for patients at risk).

In some embodiments, the composition should be formulated such that a dose of between 0.01 and 100mg of compound per kg of body weight per day can be administered.

In some embodiments, in a composition comprising an additional therapeutic agent, the additional therapeutic agent and a compound of the present disclosure may act synergistically. In some embodiments, the amount of additional therapeutic agent will be less than that required in a monotherapy utilizing only the therapeutic agent. In such compositions, additional therapeutic agents may be administered at doses between 0.01 and 1,000^ g per kilogram of body weight per day.

The compounds of the present disclosure or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, prosthetic valves, vascular prostheses, stents, and catheters. Vascular stents, for example, have been used to overcome restenosis (restenosis of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of forming clots or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of the present disclosure. Implantable devices coated with the disclosed compounds are another embodiment of the disclosure.

Further, the present disclosure provides the following embodiments:

1. a medicament, comprising:

(ii) an antibody-binding moiety,

A target binding moiety, and

the optional presence of a linker moiety or moieties,

wherein the target binding moiety specifically binds to CD 38.

2. The agent of embodiment 1, wherein the agent has the structure of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each of a and b is independently 1 to 200;

each ABT is independently an antibody binding moiety;

l is a linker moiety connecting ABT and TBT; and is

Each TBT is independently a target binding moiety.

3. The agent of embodiment 1, wherein the agent has the structure:

or a pharmaceutically acceptable salt thereof, wherein:

each of a and b is independently 1 to 200;

each ABT is independently an antibody binding moiety;

l is a bivalent linker moiety linking ABT to TBT;

each Xaa is independently a residue of an amino acid or amino acid analog;

y is 5 to 20;

L^Ta linker moiety which is two separate residues of an amino acid or amino acid analogue and is independently a covalent bond, or is selected from C₁-C₆Aliphatic radicals or having 1 to 5 hetero atomsC₁-C₆A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R') ₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each R^cIndependently is-L^a-R′；

t is 0 to 50;

each L^aIndependently a covalent bond, or is selected from C₁-C₅₀Aliphatic radical or C having 1 to 5 hetero atoms₁-C₅₀A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Each R is independently-H, or an optionally substituted group selected from: c_1-30Aliphatic radical, C having 1 to 10 heteroatoms_1-30Heteroaliphatic radical, C_6-30Aryl radical, C_6-30Arylaliphatic radical, C having 1 to 10 heteroatoms_6-30Aryl heteroaliphatic, 5-to 30-membered heteroaryl having 1 to 10 heteroatoms and 3-to 30-membered heterocyclyl having 1 to 10 heteroatoms, or

Optionally and independently, two R groups together form a covalent bond, or:

4. The medicament according to any one of the preceding embodiments, wherein a is 1.

5. The medicament according to any one of the preceding embodiments, wherein b is 1.

6. The agent according to any one of the preceding embodiments, wherein the target binding moiety is or comprises (Xaa) y, wherein each Xaa is independently a residue of an amino acid or amino acid analog, and y is 5 to 20.

7. A medicament, comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

the optional presence of a linker moiety or moieties,

wherein the target binding moiety has the following structure:

or a salt thereof, wherein:

each Xaa is independently a residue of an amino acid or amino acid analog;

y is 5 to 20;

L^Ta linker moiety which is two separate residues of an amino acid or amino acid analogue and is independently a covalent bond, or is selected from C₁-C₆Aliphatic radical or C having 1 to 5 hetero atoms₁-C₆A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R') ₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each R^cIndependently is-L^a-R′；

t is 0 to 50;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Optionally and independently, two R groups together form a covalent bond, or:

8. The agent of any one of the preceding embodiments, wherein the antibody binding moiety can bind to two or more antibodies having different Fab regions.

9. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety can bind to an Fc region.

10. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises optionally substituted

11. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

12. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises optionally substituted

13. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

14. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises optionally substituted

15. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

16. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises optionally substituted

17. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

18. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises one or more amino acid residues.

19. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises a peptide moiety.

20. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises R^c- (Xaa) z-or

Or a salt form thereof.

21. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

22. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

23. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

24. The agent according to any one of the preceding embodiments, wherein the antibody binding moiety is or comprises

25. The agent of any one of embodiments 1-9, wherein the antibody binding moiety has R ^c- (Xaa) z-or

Or a salt form thereof.

26. The agent of any one of embodiments 1-9 and 25, wherein the antibody binding portion has a structure of DCAWHLGELVWCT or a salt form thereof, wherein the two C residues are linked by-S-.

27. The medicament according to any one of the preceding embodiments, wherein- (Xaa) y-comprises:

-Xaa^T1-Xaa^T2-(Xaa)y′-Xaa^T3-Xaa^T4-Xaa^T5-，

wherein:

y' is 0 to 8;

Xaa^T5For C whose side chain is substituted₁-C₈Aliphatic amino acids or amino acidsA residue of an analog.

28. The agent of embodiment 27, wherein y' is 4.

29. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is C whose side chain is optionally substituted₂-C₈A residue of an alkyl group.

30. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1For its side chain being unsubstituted, linear C₂-C₈A residue of an alkyl group.

31. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1For its side chain being unsubstituted, linear C₂-C₈A residue of an alkyl group.

32. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is a residue whose side chain is n-pentyl.

33. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of Ahp, Y, W, S, K or K (MePEG4 c).

34. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of Ahp.

35. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of Y.

36. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of W.

37. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of S.

38. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of K.

39. The medicament according to any one of embodiments 27 to 28, wherein Xaa^T1Is the residue of K (MePEG4 c).

40. The medicament according to any one of embodiments 27 to 38, wherein Xaa ^T2For its side chain is-CH₂-the residue of R, wherein R is optionally substituted phenyl.

41. According to any one of embodiments 27 to 38The medicament of, wherein Xaa^T2Is C whose side chain is optionally substituted₃-C₈A residue of an aliphatic group.

42. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is the residue of Y, W, Ahp, Bph, L or A.

43. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is the residue of Y.

44. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is the residue of W.

45. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is the residue of Ahp.

46. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is the residue of Bph.

47. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is a residue of L.

48. The medicament according to any one of embodiments 27 to 38, wherein Xaa^T2Is the residue of A.

49. The medicament according to any one of embodiments 27 to 48, wherein Xaa^T3Is a residue of L, Ahp, V, T, Hse or MetO 2.

50. The medicament according to any one of embodiments 27 to 48, wherein Xaa^T3Is a residue of L.

51. The medicament according to any one of embodiments 27 to 48, wherein Xaa ^T3Is the residue of Ahp.

52. The medicament according to any one of embodiments 27 to 48, wherein Xaa^T3Is the residue of V.

53. The medicament according to any one of embodiments 27 to 48, wherein Xaa^T3Is the residue of T.

54. The medicament according to any one of embodiments 27 to 48, wherein Xaa^T3Is the residue of Hse.

55. The medicament according to any one of embodiments 27 to 48, wherein Xaa^T3Is the residue of MetO 2.

56. According to implementationThe medicament of any one of embodiments 27 to 55, wherein Xaa^T4Is a residue whose side chain includes an optionally substituted aromatic group.

57. The medicament according to any one of embodiments 27 to 55, wherein Xaa^T4For its side chain is-CH₂-the residue of R, wherein R is optionally substituted phenyl.

58. The medicament according to any one of embodiments 27 to 55, wherein Xaa^T4Including optionally substituted C for its side chain₃-C₈A residue of an aliphatic group.

59. The medicament according to any one of embodiments 27 to 55, wherein Xaa^T4Residues of Bph, V or Ahp.

60. The medicament according to any one of embodiments 27 to 55, wherein Xaa^T4Is the residue of Bph.

61. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is C whose side chain is optionally substituted ₂-C₆A residue of an alkyl group.

62. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is C whose side chain is optionally substituted₂-C₆A linear alkyl residue.

63. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is a residue whose side chain is n-pentyl.

64. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Residues of Ahp, Bph, Ado, Ano, PhNle or PhNva.

65. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is the residue of Ahp.

66. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is the residue of Bph.

67. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is the residue of Ado.

68. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is a residue of Ano.

69. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is a residue of PhNle.

70. The medicament according to any one of embodiments 27 to 60, wherein Xaa^T5Is a residue of PhNva.

71. The agent of any one of embodiments 27 to 70, wherein- (Xaa) y-is or comprises:

wherein:

(Xaa)_a3Is or comprises Xaa^T1；

(Xaa)_a4Is or comprises Xaa^T2；

(Xaa)_a9Is or comprises Xaa^T3；

(Xaa)_a10Is or comprises Xaa^T4(ii) a And is

(Xaa)_a11Is or comprises Xaa^T5。

72. The medicament according to any one of embodiments 27 to 71, wherein (Xaa)_a1Is or includes A, K or K (MePEG4 c).

73. The medicament according to any one of embodiments 27 to 71, wherein (Xaa)_a1Wherein a1 is 1 and Xaa is the residue of A.

74. The medicament according to any one of embodiments 27 to 71, wherein (Xaa)_a1Wherein a1 is 1 and Xaa is a residue of K.

75. The medicament according to any one of embodiments 27 to 71, wherein (Xaa)_a1In (a 1) is 1 and Xaa is the residue of K (MePEG4 c).

76. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or comprises R, S, D, Y, A, W, K, 4Py2NH2, Cit, F3G,hCit, K (MePEG4c), RNdMe, RNMe or RNNdMe.

77. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2In (a 2) is 1 and Xaa is a residue of R, S, D, Y, W, A or S.

78. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2In (a 2) is 1 and Xaa is a residue of R, S, D, Y, W, A or S.

79. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes R.

80. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes S.

81. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes D.

82. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes Y.

83. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes A.

84. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes W.

85. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes K.

86. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes 4Py2NH 2.

87. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes Cit.

88. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes F3G.

89. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes hCit.

90. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes K (MePEG4 c).

91. According to examples 27 to75 wherein (Xaa)_a2Is or includes RNdMe.

92. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Is or includes RNMe.

93. The medicament according to any one of embodiments 27 to 75, wherein (Xaa)_a2Wherein a2 is 1 and Xaa is the residue of RNNdMe.

94. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Is or includes H, Y, S, L, A or W6N.

95. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is a residue of H, Y, S, L, A or W.

96. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of H or Y.

97. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of H.

98. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of Y.

99. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of S.

100. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of L.

101. The medicament according to any one of embodiments 27 to 93, wherein (Xaa) _a5Wherein a5 is 1 and Xaa is the residue of A.

102. The medicament according to any one of embodiments 27 to 93, wherein (Xaa)_a5In (a 5) is 1 and Xaa is the residue of W6N.

103. The medicament according to any one of embodiments 27 to 102, wherein (Xaa)_a6Is or includes D, G, R, Y, H, W, A or Y.

104. The medicament according to any one of embodiments 27 to 102, wherein (Xaa)_a6Wherein a6 is 1 and Xaa is D, G, R, Y, H, W, A or Y.

105. The medicament according to any one of embodiments 27 to 102, wherein (Xaa)_a6Wherein a6 is 1 and Xaa is D, G or R.

106. The medicament according to any one of embodiments 27 to 102, wherein (Xaa)_a6Wherein a6 is 1 and Xaa is the residue of D.

107. The medicament according to any one of embodiments 27 to 102, wherein (Xaa)_a6Wherein a6 is 1 and Xaa is the residue of A.

108. The agent of any one of embodiments 27 to 107, wherein (Xaa)_a7Is or includes G, D, E, Q, N, R, MetO2, S, Har or A.

109. The agent of any one of embodiments 27 to 107, wherein (Xaa)_a7Is or includes G, D, E, Q or N.

110. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7Wherein a7 is 1 and Xaa is the residue of G.

111. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7Wherein a7 is 1 and Xaa is the residue of D, G or A.

112. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7Wherein a7 is 1 and Xaa is the residue of D.

113. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7Wherein a7 is 1 and Xaa is the residue of E.

114. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7Wherein a7 is 1 and Xaa is the residue of N.

115. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7Wherein a7 is 1 and Xaa is the residue of Q.

116. The medicament according to any one of embodiments 27 to 107, wherein (Xaa)_a7In (a 7) is 1 and Xaa is the residue of MetO 2.

117. The agent of any one of embodiments 27-107, wherein at (X)aa)_a7Wherein a7 is 1 and Xaa is the residue of A.

118. The medicament according to any one of embodiments 27 to 117, wherein (Xaa)_a8Is or includes V, A, D, G, W, S or T.

119. The medicament according to any one of embodiments 27 to 117, wherein (Xaa)_a8In (a 8) is 1 and Xaa is the residue of V, A, D, G, W, S or T.

120. The medicament according to any one of embodiments 27 to 117, wherein (Xaa) _a8Wherein a8 is 1 and Xaa is the residue of V.

121. The medicament according to any one of embodiments 27 to 117, wherein (Xaa)_a8Wherein a8 is 1 and Xaa is the residue of A.

122. The medicament according to any one of embodiments 27 to 121, wherein (Xaa)_a12Is or includes D, A, S, G or Ahp.

123. The medicament according to any one of embodiments 27 to 121, wherein (Xaa)_a12Wherein a12 is 1 and Xaa is D, S, G or Ahp.

124. The medicament according to any one of embodiments 27 to 121, wherein (Xaa)_a12Wherein a12 is 1 and Xaa is the residue of D.

125. The medicament according to any one of embodiments 27 to 121, wherein (Xaa)_a12Wherein a12 is 1 and Xaa is the residue of A.

126. The medicament according to any one of embodiments 27 to 125, wherein (Xaa)_a13Is or includes C.

127. The medicament according to any one of embodiments 27 to 125, wherein (Xaa)_a13Wherein a13 is 1 and Xaa is a residue of C.

128. The agent of any one of embodiments 1 to 26, wherein- (Xaa) y-comprises:

-Xaa^T6-(Xaa)y′-Xaa^T7-Xaa^T8-Xaa^T9-Xaa^T10-Xaa^T11-，

wherein:

y' is 0 to 8;

Xaa^T6is its side chain isSubstituted C₁-C₈A residue of an amino acid or amino acid analog of an aliphatic group;

Xaa^T8Is a residue of proline or an amino acid analogue thereof;

129. The agent of embodiment 128, wherein y' is 1.

130. The medicament according to any one of embodiments 128 to 129, wherein Xaa^T6Side chain of (A) is-CH₂-R, wherein R is optionally substituted phenyl.

131. The medicament according to any one of embodiments 128 to 130, wherein Xaa^T6Is an amino acid residue whose amino group has the structure of-N (R) -wherein R is optionally substituted C_1-6An aliphatic group.

132. The agent of any one of embodiments 128 to 131 wherein Xaa^T6An amino acid residue whose amino group has the structure of-N (Me) -.

133. The medicament according to any one of embodiments 128 to 129, wherein Xaa^T6Is a residue of MeF, L or S.

134. The medicament according to any one of embodiments 128 to 129, wherein Xaa ^T6Is the residue of MeF.

135. The medicament according to any one of embodiments 128 to 134, wherein Xaa^T7Is a residue of L or MeF.

136. The medicament according to any one of embodiments 128 to 134, wherein Xaa^T7Is a residue of L.

137. The medicament according to any one of embodiments 128 to 136, wherein Xaa^T8Is the residue of P.

138. The medicament according to any one of embodiments 128 to 137, wherein Xaa^T9Is a residue whose side chain includes an optionally substituted aromatic group.

139. The medicament according to any one of embodiments 128 to 138, wherein Xaa^T9For its side chain is-CH₂-the residue of R, wherein R is optionally substituted phenyl.

140. The medicament according to any one of embodiments 128 to 137, wherein Xaa^T9Is C whose side chain is optionally substituted₁-C₈A residue of an aliphatic group.

141. The medicament according to any one of embodiments 128 to 137, wherein Xaa^T9Is a residue of Bph, D or S.

142. The medicament according to any one of embodiments 128 to 137, wherein Xaa^T9Is the residue of Bph.

143. The medicament according to any one of embodiments 128 to 142, wherein Xaa^T10For C whose side chain is substituted₁-C₈A residue of an aliphatic group.

144. The medicament according to any one of embodiments 128 to 142, wherein Xaa ^T10Is a residue of V or L.

145. The medicament according to any one of embodiments 128 to 142, wherein Xaa^T10Is the residue of V.

146. The medicament according to any one of embodiments 128 to 142, wherein Xaa^T10Is a residue including a substituted amino group.

147. The medicament according to any one of embodiments 128 to 142, wherein Xaa^T10Is the residue of MeG.

148. The medicament according to any one of embodiments 128 to 147, wherein Xaa^T11For the side chain thereof including optionally substitutedA residue of a substituted aromatic group.

149. The medicament according to any one of embodiments 128 to 147, wherein Xaa^T11For its side chain is-CH₂-the residue of R, wherein R is optionally substituted aryl or heteroaryl.

150. The medicament according to any one of embodiments 128 to 147, wherein Xaa^T11Is the residue of W.

151. The medicament according to any one of embodiments 128 to 147, wherein Xaa^T11Is C whose side chain is optionally substituted₁-C₈A residue of an aliphatic group.

152. The medicament according to any one of embodiments 128 to 147, wherein Xaa^T11Is the residue of R.

153. The agent of any one of embodiments 128 to 152, wherein- (Xaa) y-is or comprises:

-(Xaa)_a1-(Xaa)_a2-(Xaa)_a3-(Xaa)_a4-(Xaa)_a5-(Xaa)_a6-(Xaa)_a7-(Xaa)_a8-(Xaa)_a9-(Xaa)_a10-(Xaa)_a11-(Xaa)_a12-，

wherein:

(Xaa)_a4Is or comprises Xaa^T6；

(Xaa)_a6Is or comprises Xaa^T7；

(Xaa)_a7Is or comprises Xaa^T8；

(Xaa)_a8Is or comprises Xaa^T9；

(Xaa)_a9Is or comprises Xaa^T10(ii) a And is

(Xaa)_a10Is or comprises Xaa^T11。

154. The agent of any one of embodiments 128 to 153, wherein (Xaa)_a1Is or includes A.

155. The agent of any one of embodiments 128 to 153, wherein (Xaa)_a1Wherein a1 is 1 and Xaa is the residue of A.

156. The agent of any one of embodiments 128 to 155, wherein (Xaa)_a2Is or includes L, A or P.

157. The agent of any one of embodiments 128 to 155 wherein (Xaa)_a2Wherein a2 is 1 and Xaa is the residue of L.

158. The agent of any one of embodiments 128 to 155 wherein (Xaa)_a2Wherein a2 is 1 and Xaa is the residue of A.

159. The agent of any one of embodiments 128 to 158, wherein (Xaa)_a3Is or includes H, R or A.

160. The agent of any one of embodiments 128 to 158, wherein (Xaa)_a3Wherein a3 is 1 and Xaa is the residue of H, R or A.

161. The agent of any one of embodiments 128 to 158, wherein (Xaa)_a3Wherein a3 is 1 and Xaa is the residue of H, R or A.

162. The agent of any one of embodiments 128 to 158, wherein (Xaa)_a3Wherein a3 is 1 and Xaa is the residue of H.

163. The agent of any one of embodiments 128 to 158, wherein (Xaa)_a3Wherein a3 is 1 and Xaa is the residue of A.

164. The agent of any one of embodiments 128 to 163, wherein (Xaa)_a5Is or includes V, A or MeG.

165. The medicament according to any one of embodiments 128 to 163, wherein (Xaa)_a5In (a 5) is 1 and Xaa is the residue of V, A or MeG.

166. The medicament according to any one of embodiments 128 to 163, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of V.

167. The medicament according to any one of embodiments 128 to 163, wherein (Xaa)_a5Wherein a5 is 1 and Xaa is the residue of A.

168. The agent of any one of embodiments 128 to 167, wherein (Xaa)_a11Is or includes V, A, D or MeG.

169. The agent of any one of embodiments 128 to 167, wherein (Xaa)_a11In (a 11) is 1 and Xaa is the residue of V, A, D or MeG.

170. The agent of any one of embodiments 128 to 167, wherein (Xaa)_a11Wherein a11 is 1 and Xaa is the residue of V.

171. The agent of any one of embodiments 128 to 167, wherein (Xaa)_a11Wherein a11 is 1 and Xaa is the residue of A.

172. The agent of any one of embodiments 128 to 167, wherein (Xaa) _a12Is or includes C.

173. The agent of any one of embodiments 128 to 167, wherein (Xaa)_a12Wherein a12 is 1 and Xaa is a residue of C.

174. The medicament of any one of embodiments 27 to 173, wherein two Xaa are linked together.

175. The agent of any one of embodiments 27 to 174, wherein two Xaa are via a c- (o) -CH₂-the linkers of the structure are linked together.

176. The agent of embodiment 175, wherein-c (o) -amino bonded to Xaa.

177. The agent of embodiment 176, wherein Xaa is the N-terminal residue.

178. The agent of any one of embodiments 175-177, wherein-CH₂-S-bonded to the side chain of Xaa.

179. The agent of embodiment 178, wherein Xaa is a C-terminal residue.

180. The agent of embodiment 178 or 179, wherein Xaa is C.

181. The agent of any one of embodiments 1-127 and 174-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

182. The agent of any one of embodiments 1-127 and 174-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

183. The agent of any one of embodiments 1-127 and 174-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

184. The agent of any one of embodiments 1-127 and 174-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

185. The agent of any one of embodiments 1-127 and 174-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

186. The agent of any one of embodiments 1-26 and 128-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

187. The agent of any one of embodiments 1-26 and 128-180, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

188. The agent according to any one of embodiments 1 to 26, wherein the target binding moiety or- (Xaa) y-is or comprises a peptide of:

189. The agent according to any one of embodiments 1 to 26, wherein the target binding moiety or- (Xaa) y-is or comprises a peptide of:

Ala Arg Ahp Tyr His Asp Gly Val Leu Bph Ahp Asp Cys(SEQ ID NO.1)，

Ala Leu His MePhe Val Leu Pro Bph Val Trp Val Cys(SEQ ID NO.2)；

190. The agent according to any one of embodiments 1 to 26 wherein the binding moiety of interest or- (Xaa) y-is or includes a peptide having an amino acid sequence of any one of SEQ ID No. 1-34.

191. The agent of any one of embodiments 188 to 190, wherein the target binding moiety or- (Xaa) y-has a cyclized structure.

192. The agent of any one of embodiments 1 to 26, wherein the target binding moiety is derived from, or

The following are: a structure selected from S-1 to S-39 or a pharmaceutically acceptable salt thereof.

193. The medicament of embodiment 192, wherein the structure is S-1 or a pharmaceutically acceptable salt thereof.

194. The medicament of embodiment 192, wherein the structure is S-2 or a pharmaceutically acceptable salt thereof.

195. The medicament of embodiment 192, wherein the structure is S-3 or a pharmaceutically acceptable salt thereof.

196. The medicament of embodiment 192, wherein the structure is S-4 or a pharmaceutically acceptable salt thereof.

197. The medicament of embodiment 192, wherein the structure is S-5 or a pharmaceutically acceptable salt thereof.

198. The medicament of embodiment 192, wherein the structure is S-6 or a pharmaceutically acceptable salt thereof.

199. The medicament of embodiment 192, wherein the structure is S-7 or a pharmaceutically acceptable salt thereof.

200. The medicament of embodiment 192, wherein the structure is S-8 or a pharmaceutically acceptable salt thereof.

201. The medicament of embodiment 192, wherein the structure is S-9 or a pharmaceutically acceptable salt thereof.

202. The medicament of embodiment 192, wherein the structure is S-10 or a pharmaceutically acceptable salt thereof.

203. The medicament of embodiment 192, wherein the structure is S-11 or a pharmaceutically acceptable salt thereof.

204. The medicament of embodiment 192, wherein the structure is S-12 or a pharmaceutically acceptable salt thereof.

205. The medicament of embodiment 192, wherein the structure is S-13 or a pharmaceutically acceptable salt thereof.

206. The medicament of embodiment 192, wherein the structure is S-14 or a pharmaceutically acceptable salt thereof.

207. The medicament of embodiment 192, wherein the structure is S-15 or a pharmaceutically acceptable salt thereof.

208. The medicament of embodiment 192, wherein the structure is S-16 or a pharmaceutically acceptable salt thereof.

209. The medicament of embodiment 192, wherein the structure is S-17 or a pharmaceutically acceptable salt thereof.

210. The medicament of embodiment 192, wherein the structure is S-18 or a pharmaceutically acceptable salt thereof.

211. The medicament of embodiment 192, wherein the structure is S-19 or a pharmaceutically acceptable salt thereof.

212. The medicament of embodiment 192, wherein the structure is S-20 or a pharmaceutically acceptable salt thereof.

213. The medicament of embodiment 192, wherein the structure is S-21 or a pharmaceutically acceptable salt thereof.

214. The medicament of embodiment 192, wherein the structure is S-22 or a pharmaceutically acceptable salt thereof.

215. The medicament of embodiment 192, wherein the structure is S-23 or a pharmaceutically acceptable salt thereof.

216. The medicament of embodiment 192, wherein the structure is S-24 or a pharmaceutically acceptable salt thereof.

217. The medicament of embodiment 192, wherein the structure is S-25 or a pharmaceutically acceptable salt thereof.

218. The medicament of embodiment 192, wherein the structure is S-26 or a pharmaceutically acceptable salt thereof.

219. The medicament of embodiment 192, wherein the structure is S-27 or a pharmaceutically acceptable salt thereof.

220. The medicament of embodiment 192, wherein the structure is S-28 or a pharmaceutically acceptable salt thereof.

221. The medicament of embodiment 192, wherein the structure is S-29 or a pharmaceutically acceptable salt thereof.

222. The medicament of embodiment 192, wherein the structure is S-30 or a pharmaceutically acceptable salt thereof.

223. The medicament of embodiment 192, wherein the structure is S-31 or a pharmaceutically acceptable salt thereof.

224. The medicament of embodiment 192, wherein the structure is S-32 or a pharmaceutically acceptable salt thereof.

225. The medicament of embodiment 192, wherein the structure is S-33 or a pharmaceutically acceptable salt thereof.

226. The medicament of embodiment 192, wherein the structure is S-34 or a pharmaceutically acceptable salt thereof.

227. The medicament of embodiment 192, wherein the structure is S-35 or a pharmaceutically acceptable salt thereof.

228. The medicament of embodiment 192, wherein the structure is S-36 or a pharmaceutically acceptable salt thereof.

229. The medicament of embodiment 192, wherein the structure is S-37 or a pharmaceutically acceptable salt thereof.

230. The medicament of embodiment 192, wherein the structure is S-38 or a pharmaceutically acceptable salt thereof.

231. The medicament of embodiment 192, wherein the structure is S-39 or a pharmaceutically acceptable salt thereof.

232. The medicament of any one of the preceding embodiments, comprising a linker.

233. The agent of any one of the preceding embodiments, wherein the linker is or comprises- (CH)₂CH₂O) n-where n is 1 to 20.

234. The agent of any one of the preceding embodiments, wherein the linker is or comprises- (CH)₂CH₂O) n-where n is about 5 to 20.

235. The agent of any one of the preceding embodiments, wherein the linker is or comprises- (CH)₂CH₂O) n-where n is about 10 to 20.

236. The agent of any one of the preceding embodiments, wherein the linker comprises one or more amino acid residues.

237. The agent of any one of the preceding embodiments, wherein the linker comprises one or more natural amino acid residues.

238. The agent of any one of the preceding embodiments, wherein the linker comprises one or more unnatural amino acid residues.

239. The agent of any one of the preceding embodiments, wherein the linker comprises one or more D-amino acid residues.

240. The agent of any one of the preceding embodiments, wherein the linker is or comprises a glycine residue.

241. The agent of any one of the preceding embodiments, wherein the linker is or comprises a β -alanine residue.

242. The agent of any one of the preceding embodiments, wherein the linker is or comprises a linker having-c (o) - (CH)₂CH₂O)n-CH₂CH₂NR' -structure or a salt form thereof, wherein n is 0 to 20.

243. The agent of any one of the preceding embodiments, wherein the linker is or comprises a linker having-c (o) - (CH)₂CH₂O)n-CH₂CH₂NR' -structure or a salt form thereof, wherein n is 0 to 12.

244. The agent of any one of embodiments 242-243, wherein R' is-H.

245. The agent of any one of the preceding embodiments, wherein the linker is or comprises-Gly-.

246. The agent of any one of the preceding embodiments, wherein the linker is or comprises

247. The agent of any one of the preceding embodiments, wherein the linker comprises a cycloaddition product moiety.

248. The medicament of any of the preceding embodiments, wherein the linker comprises

249. A medicament, wherein the medicament is I-3 or a pharmaceutically acceptable salt thereof.

250. A medicament, wherein the medicament is I-5 or a pharmaceutically acceptable salt thereof.

251. A pharmaceutical agent, wherein the pharmaceutical agent is I-6 or a pharmaceutically acceptable salt thereof.

252. A medicament, wherein the medicament is I-7 or a pharmaceutically acceptable salt thereof.

253. A medicament, wherein the medicament is I-8 or a pharmaceutically acceptable salt thereof.

254. A medicament, wherein the medicament is I-9 or a pharmaceutically acceptable salt thereof.

255. A pharmaceutical agent, wherein the pharmaceutical agent is I-10 or a pharmaceutically acceptable salt thereof.

256. A pharmaceutical agent, wherein the pharmaceutical agent is I-11 or a pharmaceutically acceptable salt thereof.

257. A pharmaceutical agent, wherein the pharmaceutical agent is I-12 or a pharmaceutically acceptable salt thereof.

258. A pharmaceutical agent, wherein the pharmaceutical agent is I-13 or a pharmaceutically acceptable salt thereof.

259. A medicament, wherein the medicament is I-15 or a pharmaceutically acceptable salt thereof.

260. A pharmaceutical agent, wherein the pharmaceutical agent is I-16 or a pharmaceutically acceptable salt thereof.

261. A medicament, wherein the medicament is I-17 or a pharmaceutically acceptable salt thereof.

262. A pharmaceutical agent, wherein the pharmaceutical agent is I-19 or a pharmaceutically acceptable salt thereof.

263. A pharmaceutical agent, wherein the pharmaceutical agent is I-24 or a pharmaceutically acceptable salt thereof.

264. The medicament of any one of embodiments 248-263, wherein

Is composed of

265. The medicament of any one of embodiments 248-264, wherein

Is composed of

266. A medicament, wherein the medicament is I-1 or a pharmaceutically acceptable salt thereof.

267. A medicament, wherein the medicament is I-2 or a pharmaceutically acceptable salt thereof.

268. A pharmaceutical agent, wherein the pharmaceutical agent is I-4 or a pharmaceutically acceptable salt thereof.

269. A pharmaceutical agent, wherein the pharmaceutical agent is I-14 or a pharmaceutically acceptable salt thereof.

270. A pharmaceutical agent, wherein the pharmaceutical agent is I-18 or a pharmaceutically acceptable salt thereof.

271. A medicament, wherein the medicament is I-25 or a pharmaceutically acceptable salt thereof.

272. A pharmaceutical agent, wherein the pharmaceutical agent is I-26 or a pharmaceutically acceptable salt thereof.

273. A pharmaceutical agent, wherein the pharmaceutical agent is I-27 or a pharmaceutically acceptable salt thereof.

274. A pharmaceutical agent, wherein the pharmaceutical agent is I-28 or a pharmaceutically acceptable salt thereof.

275. A pharmaceutical agent, wherein the pharmaceutical agent is I-29 or a pharmaceutically acceptable salt thereof.

276. A pharmaceutical agent, wherein the pharmaceutical agent is I-30 or a pharmaceutically acceptable salt thereof.

277. A pharmaceutical agent, wherein the pharmaceutical agent is I-31 or a pharmaceutically acceptable salt thereof.

278. A pharmaceutical agent, wherein the pharmaceutical agent is I-32 or a pharmaceutically acceptable salt thereof.

279. An agent, wherein the agent is I-33 or a pharmaceutically acceptable salt thereof.

280. A pharmaceutical agent, wherein the pharmaceutical agent is I-34 or a pharmaceutically acceptable salt thereof.

281. A pharmaceutical agent, wherein the pharmaceutical agent is I-35 or a pharmaceutically acceptable salt thereof.

282. A pharmaceutical agent, wherein the pharmaceutical agent is I-36 or a pharmaceutically acceptable salt thereof.

283. An agent, wherein the agent is I-37 or a pharmaceutically acceptable salt thereof.

284. A pharmaceutical agent, wherein the pharmaceutical agent is I-38 or a pharmaceutically acceptable salt thereof.

285. A medicament, wherein the medicament is I-39 or a pharmaceutically acceptable salt thereof.

286. A pharmaceutical agent, wherein the pharmaceutical agent is I-40 or a pharmaceutically acceptable salt thereof.

287. A pharmaceutical agent, wherein the pharmaceutical agent is I-41 or a pharmaceutically acceptable salt thereof.

288. A pharmaceutical agent, wherein the pharmaceutical agent is I-42 or a pharmaceutically acceptable salt thereof.

289. A pharmaceutical agent, wherein the pharmaceutical agent is I-43 or a pharmaceutically acceptable salt thereof.

290. A pharmaceutical agent, wherein the pharmaceutical agent is I-44 or a pharmaceutically acceptable salt thereof.

291. A medicament, wherein the medicament is I-45 or a pharmaceutically acceptable salt thereof.

292. A pharmaceutical agent, wherein the pharmaceutical agent is I-46 or a pharmaceutically acceptable salt thereof.

293. A medicament, wherein the medicament is I-47 or a pharmaceutically acceptable salt thereof.

294. The agent of any one of the preceding embodiments, wherein the agent specifically binds to CD38 as measured by SPR.

295. The agent of any one of the preceding embodiments, wherein the agent binds to CD38 with a Kd of no more than 200, 100, 50, 40, 30, 20, 10, or 5nM as measured by SPR.

296. The agent according to any one of the preceding embodiments, wherein the agent binds to CD38 as measured under the conditions described in the specification.

297. The agent according to any one of the preceding embodiments, wherein the agent binds to CD38 as measured under the conditions described in the examples.

298. The agent of any one of the preceding embodiments, wherein the agent recruits antibodies to target cells expressing CD 38.

299. The agent of any one of the preceding embodiments, wherein the agent provides a lesser reduction in non-diseased effector cells expressing CD38 as compared to the CD38 antibody.

300. A composition comprising an agent according to any one of the preceding embodiments and a population of cells.

301. The composition of embodiment 300, wherein the cell is a manipulated cell.

302. The composition of any one of embodiments 300 to 301, wherein the cell is a manufactured cell.

303. The composition of any one of embodiments 300-302, wherein the cells are suitable for cell-based therapy.

304. The composition of any one of embodiments 300 to 303, wherein the cell is or comprises an NK cell.

305. The composition of any one of embodiments 300 to 304, wherein the cell is or comprises an engineered NK cell.

306. The composition of any one of embodiments 300 to 305, wherein the cells are or comprise ex vivo expanded NK cells.

307. The composition of any one of embodiments 300 to 306, wherein the cells are or comprise memory-like NK cells.

308. The composition of any one of embodiments 300 to 307, wherein the cells are or comprise cytokine-induced memory-like NK cells.

309. The composition of any one of embodiments 300 to 303, wherein the cell is or comprises an NKT cell.

310. The composition of any one of embodiments 300 to 303, wherein the cell is or comprises a monocyte.

311. The composition of any one of embodiments 300 to 303, wherein the cell is or comprises a macrophage.

312. A pharmaceutical composition comprising an agent or composition according to any of the preceding embodiments and a pharmaceutically acceptable carrier.

313. The composition of any one of embodiments 300 to 312, wherein the composition comprises an immunoglobulin.

314. The composition of embodiment 313, wherein the immunoglobulin is or comprises an IgG.

315. The composition of any one of embodiments 313-314, wherein the immunoglobulin is an intravenous immunoglobulin.

316. The composition of any one of embodiments 313-315, wherein the immunoglobulin is an antibody against a particular antigen.

317. The composition of any of the preceding embodiments, wherein the composition is cryopreserved.

318. A method for treating a CD 38-associated condition, disorder or disease comprising administering to a subject suffering from the CD 38-associated condition, disorder or disease an effective amount of an agent or composition according to any of the preceding embodiments.

319. The method of embodiment 318, comprising administering to the subject a population of cells.

320. The method of embodiment 319, wherein the subject is subjected to both the agent or composition and the population of cells.

321. The method of any one of embodiments 319 to 320, wherein the cell is a manipulated cell.

322. The method of any one of embodiments 319 to 321, wherein the cell is a manufactured cell.

323. The method of any one of embodiments 319 to 322, wherein the cells are suitable for cell-based therapy.

324. The method of any one of embodiments 319 to 323, wherein the cell is an NK cell.

325. The method of any one of embodiments 319 to 324, wherein the cell is an engineered NK cell.

326. The method of any one of embodiments 319 to 325, wherein the cells are ex vivo expanded NK cells.

327. The method of any one of embodiments 319 to 326, wherein the cells are memory-like NK cells.

328. The method of any one of embodiments 319 to 327, wherein the cells are cytokine-induced memory-like NK cells.

329. The method according to any one of embodiments 319 to 323, wherein the cells are NKT cells.

330. The method of any one of embodiments 319 to 323, wherein the cell is a monocyte.

331. The method of any one of embodiments 319-323, wherein the cell is a macrophage.

332. The method of any one of embodiments 319-331, wherein the cell is administered concurrently with the agent or composition.

333. The method of any one of embodiments 319-332, wherein the cell and the agent or composition are administered simultaneously in the form of a composition comprising the cell and the agent or composition.

334. The method of any one of embodiments 319 to 331, wherein the cells are administered prior to administration of the agent or composition.

335. The method of any one of embodiments 319 to 331, wherein the cells are administered after administration of the agent or composition.

336. The method of any one of embodiments 318 to 335, wherein the method comprises administering an immunoglobulin.

337. The method of any one of embodiments 319 to 335, wherein the method comprises administering an immunoglobulin.

338. The method of any one of embodiments 336 to 337, wherein the immunoglobulin is or comprises IgG.

339. The method of any one of embodiments 336-338, wherein the immunoglobulin is an intravenous immunoglobulin.

340. The method of any one of embodiments 336 to 339, wherein the immunoglobulin is an antibody against a specific antigen.

341. The method of any one of embodiments 336-340, wherein the immunoglobulin is administered concurrently with the agent or composition.

342. The method of any one of embodiments 336-341, wherein the immunoglobulin and the agent or composition are administered simultaneously in the form of a composition comprising the immunoglobulin and the agent or composition.

343. The method of any one of embodiments 336-340, wherein the immunoglobulin is administered before or after the agent or composition.

344. The method of any one of embodiments 337-343, wherein the immunoglobulin is administered concurrently with the cells.

345. The method of any one of embodiments 336-339, wherein the immunoglobulin is administered simultaneously with the cell in a composition comprising the immunoglobulin and the cell.

346. The method of any one of embodiments 336-339, wherein the immunoglobulin is administered before or after the cell.

347. The method according to any of the preceding embodiments, wherein one or more doses of the cells according to any of the preceding embodiments and/or one or more doses of the cells according to any of the preceding embodiments and the agent according to any of the preceding embodiments are administered after administration of the agent.

348. The method of embodiment 347, wherein administration of the agent is a single dose of the agent.

349. The method of any one of embodiments 347 to 348, wherein one or more doses of the cells of any one of the preceding embodiments are administered after administration of the agent.

350. The method of any one of embodiments 347 to 349, wherein one or more doses of the cell according to any one of the preceding embodiments and the agent according to any one of the preceding embodiments are administered after administration of the agent.

351. The method of any one of embodiments 347-350, wherein for each dose of cells and agent, the cells are administered independently before, simultaneously with, or after the agent.

352. The method of any one of embodiments 347-350, wherein the cells and agent are administered in the same composition for at least one dose of the cells and agent.

353. A method, comprising:

a) providing a first compound comprising a target binding moiety as described in any one of the preceding embodiments and a first reactive group;

b) providing a second compound comprising an antibody binding moiety as described in any one of the preceding embodiments and a second reactive group; and

354. The method of embodiment 353, wherein the reaction between the first reactive group and the second reactive group is or comprises an amidation reaction.

355. The method of embodiment 354, wherein one of the first reactive group and the second reactive group is or comprises

And the other is or comprises-NH₂。

356. The method of embodiment 353, wherein the reaction between the first reactive group and the second reactive group is a cycloaddition reaction.

357. The method of any one of embodiments 353-356, wherein the first compound is a compound of formula V or a salt thereof.

358. The method of any one of embodiments 353-357, wherein the first compound is a compound of formula V or a salt thereof, wherein

As described in any of the preceding embodiments

359. The method of any one of embodiments 353-358, wherein the second compound is a compound of formula IV, IV-a, IV-b, IV-c, or IV-d, or a salt thereof.

360. A method for manufacturing the agent or composition according to any one of the preceding embodiments, comprising reacting a first compound comprising the antibody-binding moiety and the alkyne with a second compound comprising the target-binding moiety and the azide, or reacting a first compound comprising the antibody-binding moiety and the azide with a second compound comprising the target-binding moiety and the alkyne.

361. The method of embodiment 360, wherein the alkyne is a ring strain activated alkyne.

362. The method of embodiment 360, wherein the alkyne is an alkyne within an 8-membered ring.

363. The method of embodiment 360, wherein the alkyne is an alkyne of a BCN moiety.

364. The process of any one of embodiments 360 to 363, wherein the reaction is carried out in the absence of a copper salt.

365. A method for recruiting an antibody to a target comprising or expressing CD38, comprising contacting the target with an agent or composition according to any of the preceding embodiments.

366. A method for recruiting immune activity to a target comprising or expressing CD38, comprising contacting the target with an agent according to any of the preceding embodiments.

367. The method of any one of embodiments 365-366, wherein the target is a tumor cell.

Example

As depicted in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. It is to be understood that while the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art may be applicable to all compounds as described herein and to subclasses and classes of each of these compounds.

Example 1. exemplary Synthesis of Compounds.

Exemplary preparation of I-1.

Peptide synthesis: the peptides were synthesized using standard Fmoc chemistry. An exemplary procedure is described below.

1) In N₂DCM was added to a vessel containing the CTC resin (0.300mmol, 300mg, 1.00mmol/g) and Fmoc-Thr (tBu) -OH (95.3mg, 0.240mmol, 0.80eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.30mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

7) Fmoc-amino acid solution was added first and mixed for 30 seconds, then activation solution was added, and the reaction was continued for N₂The coupling reaction was continued for 1 hour with bubbling.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-PEG6-CH₂CH₂-COOH(2.00eq)	HATU (1.9eq) and DIEA (4.0eq)
			15	Fmoc-D-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
16	3-azidopropionic acid (3.00eq)	HATU (2.85eq) and DIEA (6.00eq)

In one preparation:

the synthesis scale is as follows: 0.24 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

After the last coupling, the resin was washed 3 times with MeOH and then dried in vacuo.

Peptide cleavage and purification. Various schemes may be utilized. In one example:

to a flask containing the side chain protected peptide was added the cleavage mixture (92.5% TFA/2.5% EDT/2.5% H) at room temperature₂O/2.5% TIS) and stirred for 1.5 hours.

After filtration, cold isopropyl ether was added to the solution and the peptide was collected by centrifugation (3 minutes at 3000 rpm) precipitation.

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, 200mL total)

Disulfide bond via I₂MeOH formation, with completion of the reaction indicated by LCMS.

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(35.0 mg).

A mixture of compound 3(5.0mg, 1.0eq) and compound 2(4.55mg, 1.0eq) was dissolved in DMF (0.5mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1482.3, 1112.2, 890.1, 741.8, etc.) were combined and lyophilized to give I-1 as a white solid (4.1mg, 42.9% yield, 95.4% purity). And (3) purification conditions:

Exemplary preparation of I-2.

Exemplary peptide synthesis. Peptides were synthesized using standard Fmoc chemistry, for example:

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.30mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.24 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

After the last amino acid coupling, the N-terminal Fmoc was removed and the resin was washed 3 times with MeOH and then dried in vacuo.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, 200mL total)

The reaction mixture was lyophilized to give the crude peptide.

A mixture of Compound 2(35.0mg, 1.0 equiv.) and DBCO-NHS (7.66mg, 1.1 equiv.) was dissolved in DMF (1.0mL) and DIEA (6.00 eq.) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (11.0mg, 32.4% yield).

Compound 4 was prepared by reacting the corresponding peptide dissolved in DMF (0.5mL) with 3-azidopropionic acid-NHS (0.97mg, 1.1 eq). DIEA (6.0eq) was then added slowly. The mixture was stirred at 20 ℃ for 2 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 4 was obtained as a white solid (5.50mg, 52.4% yield).

A mixture of compound 4(5.5mg, 1.0eq) and compound 3(5.10mg, 1.0eq) was dissolved in DMF (0.5mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1600.3, 1200.4, 960.5, etc.) were combined and lyophilized to give I-2 as a white solid (4.1mg, 38.7% yield, 95.7% purity). And (3) purification conditions:

exemplary preparation of I-3.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.30mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.24 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, 200mL total)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(45.0 mg).

A mixture of Compound 2(45.0mg, 1.0eq) and BCN-NHS (6.48mg, 1.1eq) was dissolved in DMF (1.0mL) and DIEA (6.0eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (14.0mg, 28.6% yield).

A mixture of compound 3(14.0mg, 1.0eq) and compound 75(12.7mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1049.9, 840.0, 700.4, etc.) were combined and lyophilized to give I-3 as a white solid (11.1mg, 41.6% yield, 97.1% purity). And (3) purification conditions:

exemplary preparation of I-4.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.30mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-PEG8-CH₂CH₂-COOH(2.00eq)	HATU (1.9eq) and DIEA (4.0eq)
			15	Fmoc-D-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
16	Fmoc-D-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)

The synthesis scale is as follows: 0.24mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H ₂O (1: 1, 200mL total)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(48.0 mg).

A mixture of Compound 2(48.0mg, 1.0eq) and BCN-NHS (9.37mg, 1.1eq) was dissolved in DMF (1.0mL) and DIEA (6.0eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (14.0mg, 28.6% yield).

A mixture of compound 3(14.0mg, 1.0eq) and compound 75(11.0mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1138.6, 911.2, 759.4, etc.) were combined and lyophilized to give I-4 as a white solid (15.9mg, 63.3% yield, 96.6% purity). And (3) purification conditions:

exemplary preparation of I-5.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.30mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-A1a-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-PEG3-CH₂CH₂-COOH(2.00eq)	HATU (1.9eq) and DIEA (4.0eq)
			15	Fmoc-D-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)

The synthesis scale is as follows: 0.24mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, 200mL total)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O，B: ACN) to give compound 2(42.0 mg).

A mixture of Compound 2(42.0mg, 1.0eq) and BCN-NHS (7.11mg, 1.1eq) was dissolved in DMF (1.0mL) and DIEA (6.0eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (15.0mg, 32.7% yield).

A mixture of compound 4(13.5mg, 1.0eq) and compound 3(15.0mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 983.8, 787.6, etc.) were combined and lyophilized to give I-5 as a white solid (10.5mg, 36.8% yield, 95.1% purity). And (3) purification conditions:

exemplary preparation of I-6.

Compound 1(2.00g, 4.37mmol), Fmoc-NH-PEG₃-CH₂CH₂N₃A mixture of (1.00g, 4.59mmol), EDCI (1.68g, 8.74mmol), HOBt (1.18g, 8.74mmol) was dissolved in DCM (20.0mL) and the reaction was stirred at 15 ℃ for 16 h. The solution was then diluted with DCM (100mL) and 1M HCl (30mL), H₂O (30mL), brine (30mL), over anhydrous Na₂SO₄Drying and concentration under reduced pressure gave compound 2(3.00g, crude material) as a colorless oil.

With TFA/H at 15 deg.C₂Compound 2(3.00g, crude material) was treated with O (95/5, ca. 20mL) for 1 hour. The solvent was then removed under reduced pressure and chromatographed by flash C18 (C)

120g

C18 flash column, eluent: 0 to 100% MeCN/H₂O, 75mL/min) to give compound 3 as a white solid (1.50g, 2.24mmol, 49.2% yield).

1) DCM (10.0mL) was added to a vessel containing the CTC resin (2.0mmol, 2.0g, 1.0mmol/g) and Fmoc-Asp (OtBu) -OH (658mg, 1.60mmol, 0.80eq) with N2 bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (2.0mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

7) Fmoc-amino acid solution was added first and mixed for 30 seconds, then activation buffer was added, and the reaction was continued for N₂The coupling reaction was continued for 1 hour with bubbling.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Step (ii) of	Material	Coupling reagent
			1	Fmoc-Asp(OtBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-HomoNle-OH(2.00eq)	HATU (1.90eq) and DIEA (4.00eq)
			3	Fmoc-Bip-OH(2.00eq)	HATU (1.90eq) and DIEA (4.00eq)
4	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Asp(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-Tyr(tBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-HomoNle-OH(2.00eq)	HATU (1.90eq) and DIEA (4.00eq)
			11	Fmoc-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Compound 3(2.00eq)	HATU (1.90eq) and DIEA (4.00eq)

The synthesis scale is as follows: 1.6mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

After coupling, the Fmoc group was removed and the resin was washed 3 times with MeOH and then dried in vacuo.

Peptide cleavage and purification:

to the flask containing the side chain protected peptide was added the lysis solution (20% HFIP/DCM, 80mL) at room temperature. Cracking in continuous N₂Bubbling was performed twice (30 minutes each).

After filtration, the filtrate was concentrated under reduced pressure, and the residue was dried in a lyophilizer to give compound 4(2.9g, crude material) as a white solid.

A solution of compound 4(2.9g, 1.0eq), HOBt (308mg, 2.0eq), TBTU (732mg, 2.0eq), DIEA (0.85mL, 4.0eq) in DMF (800mL) was stirred at 15 ℃ for 1 hour. When cyclization was complete, the solution was then diluted with EA (1.5L), washed with 1M HCl (600mL), brine (400 mL. times.4), and dried over anhydrous Na₂SO₄Drying and concentration under reduced pressure gave compound 5(3.2g, crude material) as a colorless oil.

The resulting mixture was stirred continuously at 15 ℃ for 1.5 hours with TFA/TIS/H₂Deprotection of the crude cyclic peptide was performed by O (95/2.5/2.5, 40mL total) treatment of Compound 5(3.2g, crude material). The solution was wet milled with cold isopropyl ether (500mL) and the precipitate was collected by centrifugation (3 minutes at 3000 rpm). The precipitate (deprotected peptide) was washed twice with isopropyl ether (50 mL each) and then dried in vacuo for 2 h. The residue was purified by preparative HPLC (acidic conditions, TFA) to give compound 6(600 mg).

Another example is:

1) in N₂DCM was added to a vessel containing the CTC resin (0.500mmol, 500mg, 1.00mmol/g) and Fmoc-Thr (tBu) -OH (159mg, 0.400mmol, 0.80eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-PEG3-CH₂CH₂COOH(2.00eq)	HATU (1.90eq) and DIEA (4.0eq)
			15	Fmoc-D-Lys(Dde)-OH(2.00eq)	HATU (1.90eq) and DIEA (4.0eq)
16	Fmoc-PEG3-CH₂CH₂COOH(2.00eq)	HATU (1.90eq) and DIEA (4.0eq)
			17	Boc-D-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
18	Palmitic acid (3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)

The synthesis scale is as follows: 0.4mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

After

cycle

17, 3% NH₂NH₂H₂O/DMF was used to remove Dde and then to couple palmitic acid to the side chain of D-Lys.

Peptide cleavage and purification:

to a flask containing the side chain protected peptide was added the cleavage mixture (92.5% TFA/2.5% EDT/2.5% H) at room temperature₂O/2.5% TIS) and stirred for 2 hours.

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O(1∶1，Total 600mL) in

Disulfide bond via I₂MeOH was formed and stirred for 20 minutes, with completion of the reaction indicated by LCMS.

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 8(55.0 mg).

A mixture of compound 8(55.0mg, 1.0eq) and BCN-NHS (7.20mg, 1.1eq) was dissolved in DMF (1mL) and DIEA (6.0eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 9 was obtained as a white solid (19.0mg, 32.0% yield).

A mixture of compound 9(19.0mg, 1.0eq) and compound 6(13.5mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1126.0, 901.2, 751.1, etc.) were combined and lyophilized to give I-6 as a white solid (12.7mg, 39.2% yield, 92.4% purity). And (3) purification conditions:

exemplary preparation of I-7.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-Gly-Gly-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
			15	Fmoc-Lys(Dde)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
16	Fmoc-Glu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			17	Fmoc-Ser(tBu)-Ser[psiMe，-Mepro]-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
18	Fmoc-Gly-Gly-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
			19	Boc-D-Arg(Pbf)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
20	Palmitic acid (3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)

The synthesis scale is as follows: 0.4mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

After the 19 th cycle, 3% NH₂NH₂H₂O/DMF was used to remove Dde and then to couple palmitic acid to the side chain of Lys.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 600mL)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(63.0 mg).

A mixture of Compound 2(63.0mg, 1.0eq) and BCN-NHS (7.47mg, 1.1eq) was dissolved in DMF (1mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (20.0mg, 29.8% yield).

A mixture of compound 3(20.0mg, 1.0eq) and compound 75(13.9mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1219.3, 975.4, etc.) were combined and lyophilized to give I-7 as a white solid (11.7mg, 34.5% yield, 96.8% purity). And (3) purification conditions:

Exemplary preparation of I-8.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.4mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

Pd (PPh)₃)₄And phenylsilanes for De-OAll.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

to a flask containing the side chain protected peptide was added the cleavage cocktail (95% TFA/2.5% EDT/2.5% H) at room temperature ₂O/2.5% TIS) and stirred for 2 hours.

The peptide was precipitated with cold isopropyl ether and collected by centrifugation (3 minutes at 3000 rpm).

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 600mL)

By NaHCO₃The pH was adjusted to 8 and stirred for 16 hours and disulfide bonds were formed via air oxidation, with completion of the reaction indicated by LCMS.

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(75.0 mg).

A mixture of Compound 2(75.0mg, 1.0eq) and BCN-NHS (8.91mg, 1.1eq) was dissolved in DMF (2mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (35.0mg, 43.8% yield).

A mixture of compound 3(35.0mg, 1.0eq) and compound 75(24.4mg, 1.0eq) was dissolved in DMF (2.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1218.3, 974.8, 812.2, etc.) were combined and lyophilized to give I-8 as a white solid (29.3mg, 49.7% yield, 97.6% purity). And (3) purification conditions:

Exemplary preparation of I-9.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-Gly-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
			15	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
16	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			17	Fmoc-D-Glu(OAll)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
18	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			19	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
20	Fmoc-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			21	Fmoc-piperidine-4-carboxylic acid (3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
22	12-Aminododecanoic acid tert-butyl ester (3.00eq)	HOAt (3.0eq) and DIC (3.00eq)

The synthesis scale is as follows: 0.4mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

Pd (PPh)₃)₄And phenylsilane was used to remove the aly group on the side chain of D-Glu.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

to a flask containing the side chain protected peptide was added the cleavage cocktail (95% TFA/2.5% EDT/2.5% H) at room temperature₂O/2.5% TIS) and stirred for 2 hours.

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 600mL)

By NaHCO₃The pH was adjusted to 8 and stirred for 16 hours, and the first disulfide bond was formed via air oxidation, with completion of the reaction indicated by LCMS.

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(42.0 mg).

A mixture of Compound 2(42.0mg, 1.0eq) and BCN-NHS (5.06mg, 1.1eq) was dissolved in DMF (1mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (13.0mg, 29.0% yield).

A mixture of compound 3(13.0mg, 1.0eq) and compound 75(9.18mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1207.9, 966.8, 805.6, etc.) were combined and lyophilized to give I-9 as a white solid (10.9mg, 49.1% yield, 97.1% purity). And (3) purification conditions:

exemplary preparation of I-10.

Azide-containing compound 75(1.0eq) and the corresponding alkyne-containing compound 3(1.0eq), prepared using similar techniques described above, were dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1019.0, 849.0, etc.) were combined and lyophilized to give I-10 as a white solid (7.3mg, 33.2% yield, 98.9% purity). And (3) purification conditions:

Exemplary preparation of I-11.

1) in N₂DCM (2.00mL) was added to the CTC-containing resin (0.50mmol, 0.45g, 1.10mmol/g) and Fmoc-NH-PEG with bubbling₆-CH₂CH₂COOH (0.30g, 0.50mmol, 1.00 eq).

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Step (ii) of	Material	Coupling reagent
				1	Fmoc-NH-PEG₆-CH₂CH₂COOH(1.00eq)	DIEA(4.00eq)
2	Fmoc-Arg(Pbf)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Arg(Pbf)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Inp-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Boc₂O(3.00eq)	DIEA(6.00eq)

The synthesis scale is as follows: 0.50mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min. The coupling reaction was monitored by ninhydrin test and the resin was washed 5 times with DMF.

After the last amino acid coupling, the resin was washed 3 times with MeOH and then dried in vacuo.

Peptide cleavage:

to the flask containing the side chain protected peptide was added lysis solution (20% HFIP/DCM, 50mL) at room temperature. Cracking in continuous N ₂Bubbling was performed twice (30 minutes each).

After filtration, the filtrate was concentrated under reduced pressure, and the residue was dried in a lyophilizer to give compound 1(0.50g, crude material) as a white solid.

A solution of Compound 1(50.0mg, 36.0. mu. mol), N- [3- (3-aminopropylcarbamoyl) -4-methoxy-phenyl ] imidazo [2, 1-b ] thiazole-6-carboxamide (17.0mg, 36.3. mu. mol, TFA salt), EDCI (69.1mg, 362. mu. mol) in pyridine (0.50mL) was stirred at 25 ℃ for 16 h. Pyridine was then removed under reduced pressure to give a residue, to which TFA (1.00mL) was then added and stirred at 25 ℃ for 1 hour to remove the Boc protecting group. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (acidic conditions, TFA) to give compound 2(TFA salt, 35.0mg, 30.9 μmol, 85.4% yield) as a white solid.

A solution of Compound 2(35.0mg, 28.1. mu. mol, TFA salt), [ (1R, 8S) -9-bicyclo [6.1.0] non-4-ynyl ] methyl carbonate (2, 5-dioxopyrrolidin-1-yl) ester (12.2mg, 42.1. mu. mol), DIEA (36.3mg, 281. mu. mol, 49. mu.L) in DMF (0.20mL) was stirred at 25 ℃ for 3 hours. The solution was then purified by preparative HPLC (acidic conditions, TFA) to give compound 3(30.0mg, 22.9 μmol, 81.6% yield) as a white solid.

A solution of compound 75(39.7mg, 19.8. mu. mol), compound 3(26.0mg, 19.8. mu. mol), DIEA (10.2mg, 79.4. mu. mol, 14. mu.L) in DMF (0.70mL) was stirred at 25 ℃ for 3 hours. When the click reaction was complete (indicated by LCMS, MS observations: m/z 1102.3, 826.8, 661.6, etc.), the solution was purified directly by preparative HPLC (acidic conditions, TFA) to afford Compound I-11(29.0mg, 8.33. mu. mol, 41.9% yield, 98.4% purity) as a white solid after lyophilization. And (3) purification conditions:

exemplary preparation of I-12.

1) in N₂DCM (2.00mL) was added to the CTC-containing resin (0.50mmol, 0.45g, 1.1mmol/g) and Fmoc-NH-PEG with bubbling₆-CH₂CH₂COOH (0.30g, 0.50mmol, 1.00 eq).

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.50 mmol.

Peptide cleavage:

to the flask containing the side chain protected peptide was added lysis solution (20% HFIP/DCM, 50mL) at room temperature. Cracking in continuous N₂Bubbling was performed twice (30 minutes each).

A solution of compound 1(50.0mg, 36.1. mu. mol), 1- (3-aminopropyl) -N- [5- (2-furyl) -1, 3, 4-thiadiazol-2-yl ] -2-oxo-3H-benzimidazole-5-carboxamide (18.0mg, 36.1. mu. mol, TFA salt), EDCI (69.3mg, 362. mu. mol) in pyridine (0.50mL) was stirred at 25 ℃ for 16H. Pyridine was then removed under reduced pressure. To the residue was added TFA (1mL) and stirred at 25 ℃ for 1 hour. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (acidic conditions, TFA) to give compound 2(TFA salt, 25.0mg, 21.8 μmol, 60.4% yield) as a white solid.

A solution of Compound 2(25.0mg, 19.8. mu. mol, TFA salt), [ (1R, 8S) -9-bicyclo [6.1.0] non-4-ynyl ] methyl carbonate (2, 5-dioxopyrrolidin-1-yl) ester (5.8mg, 19.8. mu. mol), DIEA (12.8mg, 99.4. mu. mol, 18. mu.L) in DMF (0.2mL) was stirred at 25 ℃ for 3 hours. The solution was purified by preparative HPLC (acidic conditions, TFA) to give compound 3(15mg, 11.3 μmol, 57.1% yield) as a white solid.

A solution of compound 75(22.7mg, 11. mu. mol), compound 3(15.0mg, 11. mu. mol) in DMF (0.7mL) was stirred at 25 ℃ for 3 hours. The solution was purified by preparative HPLC (acidic conditions, TFA) to give I-12(25.9mg, 7.65 μmol, 67.3% yield, 98.5% purity) as a white solid. LCMS MS observations: m/z 1105.8, 829.5, 663.7 and the like. And (3) purification conditions:

exemplary preparation of I-13.

1. in N₂DCM (2.00mL) was added to the CTC-containing resin (0.50mmol, 0.45g, 1.1mmol/g) and Fmoc-NH-PEG with bubbling₆-CH₂CH₂COOH (0.30g, 0.50mmol, 1.00 eq).

2. DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3. MeOH (0.50mL) was added and mixed for 30 minutes.

4. Drained and washed 5 times with DMF.

5. 20% piperidine/DMF was added and the reaction was for 30 min.

6. Drained and washed 5 times with DMF.

7. Fmoc-amino acid solution was added first and mixed for 30 seconds, then activation buffer was added, and the reaction was continued for N₂The coupling reaction was continued for 1 hour with bubbling.

8. Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.50mmol

Peptide cleavage:

A solution of Compound 1(50.0mg, 36.1. mu. mol), 1- (3-aminopropyl) -2-methyl-N- [4- (2-pyridyl) thiazol-2-yl ] benzimidazole-5-carboxamide (14.2mg, 36.1. mu. mol, TFA salt), EDCI (69.3mg, 362. mu. mol) in pyridine (0.50mL) was stirred at 25 ℃ for 16 h. Pyridine was then removed under reduced pressure. To the residue was added TFA (1.00mL) and stirred at 25 ℃ for 1 hour to remove the Boc group. After deprotection, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (acidic conditions, TFA) to give compound 2(29.0mg, 16.5 μmol, 45.6% yield) as a white solid.

A solution of Compound 2(29.0mg, 22.9. mu. mol, TFA salt), [ (1R, 8S) -9-bicyclo [6.1.0] non-4-ynyl ] methyl carbonate (2, 5-dioxopyrrolidin-1-yl) ester (6.7mg, 22.9. mu. mol), DIEA (14.8mg, 114. mu. mol, 14.8. mu.L) in DMF (0.20mL) was stirred at 25 ℃ for 3 hours. The solution was purified by preparative HPLC (acidic conditions, TFA) to give I-13(TFA salt, 20.0mg, 15.0 μmol, 65.7% yield) as a white solid.

A solution of compound 75(30.2mg, 15.1. mu. mol), compound 3(20.0mg, 15.1. mu. mol) in DMF (0.70mL) was stirred at 25 ℃ for 3 hours. The solution was directly purified by preparative HPLC (acidic conditions, TFA) to afford I-13(27.2mg, 8.06 μmol, 53.1% yield, 99.0% purity) as a white solid after lyophilization. LCMS MS observations: 1108.6, 831.4, 665.4, etc. And (3) purification conditions:

exemplary preparation of I-14.

Compound 1(1.00g, 2.4mmol), Fmoc-NH-PEG₃-CH₂CH₂N₃A mixture of (1.10g, 2.4mmol), EDCI (688mg, 3.6mmol), HOBt (486mg, 3.6mmol) was dissolved in DCM (30.0mL) and the reaction was stirred at 15 ℃ for 16 h. The solution was then diluted with DCM (100mL) and 1M HCl (30mL), H₂O (30mL), brine (30mL), over anhydrous Na ₂SO₄Drying and concentration under reduced pressure gave compound 2(3.00g, crude material) as a colorless oil.

With TFA/H at 15 deg.C₂Compound 2(3.00g, crude material) was treated with O (95/5, ca. 20mL) for 1 hour. The solvent was then removed under reduced pressure. The solution was then diluted with DCM (100mL) and 1M HCl (30mL), H₂O (30mL), brine (30mL), over anhydrous Na₂SO₄Drying, and concentrating under reduced pressure to obtain crude material. The crude material (2.6g, 3.67mmol, 1.0eq) was first dissolved in DCM and DIEA (1.92mL, 3eq) was then added and mixed well, finally Boc was added dropwise at 25 ℃₂Solution O (1.20g, 5.51mmol, 1.27mL, 1.5eq, in 20mL DCM). The reaction mass is brought to 25 DEG CStirred for 3 hours and then chromatographed by flash C18 (

120g

C18 flash column, eluent: 0 to 100% MeCN/H₂O, 75mL/min) to give compound 3 as a white solid (1.46g, 2.24mmol, 49.2% yield).

1) in N₂DCM was added to a vessel containing the CTC resin (0.200mmol, 200mg, 1.00mmol/g) and Fmoc-Thr (tBu) -OH (63.5mg, 0.16mmol, 0.80eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.20mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.16mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

to a flask containing the side chain protected peptide was added the cleavage mixture (92.5% TFA/2.5% EDT/2.5% H2O/2.5% TIS) at room temperature and stirred for 1.5H.

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, 100mL total)

By NaHCO₃The pH was adjusted to 8 and stirred for 8 hours and disulfide bonds were formed via air oxidation, with completion of the reaction indicated by LCMS.

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 5(30.0 mg).

Another example is:

1) in N₂DCM was added to a vessel containing the CTC resin (0.500mmol, 500mg, 1.00mmol/g) and Fmoc-Thr (tBu) -OH (130mg, 0.40mmol, 0.80eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Step (ii) of	Material	Coupling reagent
			1	Fmoc-Abu-OH(0.8eq)	DIEA(4.0eq)
2	Fmoc-heptanoic acid (2.0eq)	HATU (1.9eq) and DIEA (4.0eq)
			3	Fmoc-Bip-OH(2.0eq)	HATU (1.9eq) and DIEA (4.0eq)
4	Fmoc-Leu-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			5	Fmoc-Val-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
6	Fmoc-Gly-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			7	Fmoc-Asp(tBu)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
8	Fmoc-His(Trt)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			9	Fmoc-Tyr(tBu)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
10	Fmoc-heptanoic acid (2.0eq)	HATU (1.9eq) and DIEA (4.0eq)
			11	Fmoc-Arg(Pbf)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
12	Fmoc-Ala-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			13	Compound 3(2.0eq)	HATU (1.9eq) and DIEA (4.0eq)

The synthesis scale is as follows: 0.4 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

to the flask containing the side chain protected peptide was added the lysis solution (20% HFIP/DCM, 20mL) at room temperature. Cracking in continuous N₂Bubbling was performed twice (30 minutes each).

After filtration, the filtrate was concentrated under reduced pressure, and the residue was dried in a lyophilizer to give compound 6(1.0g, crude material) as a white solid.

A solution of compound 6(1.0g, 1.0eq), HOBt (101mg, 2.0eq), TBTU (240mg, 2.0eq), DIEA (0.85mL, 4.0eq) in DMF (400mL) was stirred at 15 ℃ for 1 hour. When cyclization was complete, the solution was then diluted with EA (1.5L), washed with 1M HCl (600mL), brine (400 mL. times.4), and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give the crude material (1.1g, crude material) as a colorless oil.

The resulting mixture was stirred continuously at 15 ℃ for 1.5 hours with TFA/H₂Deprotection of the crude cyclic peptide was performed by O (97.5/2.5, 20mL total) treating the cyclized peptide (1.1g, crude). The solution was wet milled with cold isopropyl ether (250mL) and the precipitate was collected by centrifugation (3 minutes at 3000 rpm). The precipitate (deprotected peptide) was washed twice with isopropyl ether (50 mL each) and then dried in vacuo for 2 h. The residue was purified by preparative HPLC (acidic conditions, TFA) to give compound 7(150 mg).

A mixture of compound 7(150mg, 1.0eq) and 2- (4- (6-methyl-1, 2, 4, 5-tetrazin-3-yl) phenyl) acetic acid 2, 5-dioxopyrrolidin-1-yl ester (27.8mg, 1.1eq) was dissolved in DMF (4.0mL) and then DIEA (6.0eq) was slowly added. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 8 was obtained as a white solid (48mg, 28.9% yield).

A mixture of Compound 8(11.0mg, 1.0eq) and Compound 5(9.94mg, 1.0eq) was dissolved in DMF/H₂O (4: 1, 1.5mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1358.2, 1018.7, 815.4, etc.) were combined and lyophilized, yielding a white solidI-14 as (2.2mg, 10.5% yield, 76.4% purity). And (3) purification conditions:

exemplary preparation of I-15.

1) DMF was added to a resin containing Rink amide MBHA (1.00mmol, 2.27g, substrate: 0.440mmol/g) and allowed to expand for 2 hours.

2) Drained and washed 3 times with DMF.

3) Add 20% piperidine/DMF and mix for 30 min.

4) Drained and washed 3 times with DMF.

5) Fmoc-amino acid solution was added and mixed for 30 seconds, then coupling reagent was added, and the reaction was continued N₂The coupling reaction was continued for 1 hour with bubbling.

6) Repeat steps 2 through 5 for the next amino acid coupling.

The synthesis scale is as follows: 1.0mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 600mL)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(218mg, 7.46% yield).

Dissolve Compound 2(218mg) in ACN/H₂O (50.0mL), and then 1M HCl was added to adjust the pH to 1, then 0.1M I was added dropwise₂AcOH until the mixture turns brown. The mixture was then stirred at 20 ℃ for 10 hours. LCMS showed reaction completion. The mixture was purified by preparative HPLC (TFA conditions) to give compound 3(100mg, 48.2% yield) as a white solid.

A mixture of compound 3(100mg, 1.0eq) and BCN-NHS (11.5mg, 1.1eq) was dissolved in DMF (3mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 30 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 4 was obtained as a white solid (29.0mg, 27.4% yield).

A mixture of compound 4(29.0mg, 1.0eq) and compound 75(19.6mg, 1.1eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 15 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1238.0, 990.2, etc.) were combined and lyophilized to give I-15 as a white solid (30.6mg, 59.7% yield, 97.6% purity). And (3) purification conditions:

Exemplary preparation of I-16.

2) Drained and washed 3 times with DMF.

3) Add 20% piperidine/DMF and mix for 30 min.

4) Drained and washed 3 times with DMF.

6) Repeat steps 2 through 5 for the next amino acid coupling.

The synthesis scale is as follows: 1.0 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 600mL)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA)₂O, B: ACN) to give compound 2(248mg, 8.84% yield).

Compound 2(248mg) was dissolved in ACN/H₂O (50.0mL), and then 1M HCl was added to adjust the pH to 1, then 0.1M I was added dropwise₂AcOH until the mixture turns brown. The mixture was then stirred at 20 ℃ for 10 hours. LCMS showed reaction completion. Tong (Chinese character of 'tong')The mixture was purified by preparative HPLC (TFA conditions) to give compound 3(110mg, 44.4% yield) as a white solid.

A mixture of compound 3(110mg, 1.0eq) and BCN-NHS (13.2mg, 1.1eq) was dissolved in DMF (3mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 30 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 4 was obtained as a white solid (21.0mg, 17.9% yield).

A mixture of compound 4(21.0mg, 1.0eq) and compound 75(14.8mg, 1.1eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 15 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1209.4, 967.7, etc.) were combined and lyophilized to give I-16 as a white solid (20.4mg, 60.0% yield, 99.4% purity). And (3) purification conditions:

Exemplary preparation of I-17.

1) in N₂DCM was added to a vessel containing the CTC resin (1.00mmol, 1.00g, 1.00mmol/g) and Fmoc-Thr (tBu) -OH (3218mg, 0.800mmol, 0.80eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (1.00mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-Gly-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
			15	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
1 6	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			17	Fmoc-D-Glu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
18	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			19	Fmoc-D-gamaGlu(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
20	Fmoc-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			21	Fmoc-piperidine-4-carboxylic acid (3.00eq)	HATU (2.85eq) and DIEA (6.00eq)

The synthesis scale is as follows: 0.8mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 800mL)

The reaction mixture was lyophilized to give the crude peptide.

The crude peptide was purified by preparative HPLC (TFA conditions) to give compound 2(102 mg).

A mixture of compound 2(102mg, 1.0eq) and BCN-NHS (13.3mg, 1.1eq) was dissolved in DMF (2mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (43.0mg, 39.4% yield).

A mixture of compound 3(43.0mg, 1.0eq) and compound 75(32.6mg, 1.0eq) was dissolved in DMF (2.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1158.8, 927.2, 772.7, etc.) were combined and lyophilized to give I-17 as a white solid (41.1mg, 56.9% yield, 98.4% purity). And (3) purification conditions:

exemplary preparation of I-18.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.30mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 0.24 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, 200mL total)

The reaction mixture was lyophilized to give the crude peptide.

By preparative HPLC (A: H with 0.075% TFA) ₂O, B: ACN) to give compound 2(15.0 mg).

A mixture of compound 3(6.0mg, 1.0eq) and compound 2(4.93mg, 1.0eq) was dissolved in DMF (0.5mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1170.4, 939.4, 783.0, etc.) were combined and lyophilized to give I-18 as a white solid (7.1mg, 64.9% yield, 96.1% purity). And (3) purification conditions:

exemplary preparation of I-19.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.50mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-PEG8-CH₂CH₂COOH(2.00eq)	HATU (1.9eq) and DIEA (4.0eq)
			15	FMOC-O- (phenylmethylphosphato) -serine (3.00eq)	HATU (2.85eq) and DIEA (6.0eq)
16	FMOC-O- (phenylmethylphosphato) -serine (6.00eq)	HATU (5.70eq) and DIEA (12.00eq)
			20	Fmoc-Gly-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
21	Fmoc-piperidine-4-carboxylic acid (3.00eq)	HATU (2.85eq) and DIEA (6.00eq)

The synthesis scale is as follows: 0.4 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

The precipitate was washed twice more with cold isopropyl ether.

The crude peptide was dried in vacuo for 2 hours.

Dissolving the crude peptide in ACN/H₂O (1: 1, total 600mL)

The reaction mixture was lyophilized to give the crude peptide.

The crude peptide was purified by preparative HPLC (TFA conditions) to give compound 2(80.0 mg).

A mixture of Compound 2(80.0mg, 1.0eq) and BCN-NHS (10.8mg, 1.1eq) was dissolved in DMF (1mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 20 ℃ for 8 hours. LCMS showed reaction completion. The mixture was then directly purified by preparative HPLC (TFA conditions) and compound 3 was obtained as a white solid (27.0mg, 31.4% yield).

A mixture of compound 3(27.0mg, 1.0eq) and compound 75(21.2mg, 1.0eq) was dissolved in DMF (1.0mL) and the reaction was stirred at 20 ℃ for 8 h. LCMS showed the reaction was complete, and then the mixture was directly purified by preparative HPLC. Fractions with the desired m/z (e.g., 1136.3, 909.4, 757.9, etc.) were combined and lyophilized to give I-19 as a white solid (28.8mg, 59.7% yield, 90.4% purity). And (3) purification conditions:

Exemplary preparation of I-24.

1) in N₂DCM was added to a vessel containing the CTC resin (2.00mmol, 2.00g, 1.00mmol/g) and Fmoc-Cys (Trt) -OH (938mg, 1.60mmol, 0.80eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (0.10mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) Steps 4 to 7 are repeated for the next amino acid coupling.

The synthesis scale is as follows: 1.6mmol

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

to the flask containing the side chain protected peptide was added the lysis solution (20% HFIP/DCM) at room temperature. Cracking in continuous N₂Bubbling was performed twice (20 minutes each).

After filtration, the filtrate was concentrated under reduced pressure, and the residue was dried in a lyophilizer to give compound 1(3.1g, crude material) as a white solid.

Another example is:

1) in N₂DCM was added to a vessel containing CTC resin (2.00mmol, 2.00g, 1.00mmol/g) and hexane-1, 6-diamine (256mg, 2.20mmol, 1.10eq) with bubbling.

2) DIEA (4.00eq) was added dropwise and mixed for 2 hours.

3) MeOH (2.00mL) was added and mixed for 30 minutes.

4) Drained and washed 5 times with DMF.

5) 20% piperidine/DMF was added and the reaction was for 30 min.

6) Drained and washed 5 times with DMF.

8) The above steps 4 to 7 were repeated for the coupling of the following amino acids.

The synthesis scale is as follows: 2.0 mmol.

DMF with 20% piperidine was used for Fmoc deprotection for 30 min.

The coupling reaction was monitored by ninhydrin test.

Peptide cleavage and purification:

to the flask containing the side chain protected peptide was added the lysis solution (20% HFIP/DCM) at room temperature. Cracking in continuous N ₂Bubbling was performed twice (20 minutes each).

After filtration, the filtrate was concentrated under reduced pressure, and the residue was dried in a lyophilizer to give compound 2(800mg, crude material) as a white solid.

First a mixture of compound 2(500mg, 1.0eq) and compound 1(1.35g, 1.2eq) was dissolved in DMF (5.0mL), followed by the addition of HOAt (2.0eq, pre-dissolved in DMF) and DIC (2.0 eq). The mixture was stirred at 30 ℃ for 8 hours until LCMS appearedIndicating that the coupling is complete. The mixture was concentrated under reduced pressure to remove the solvent. To the crude material was added 30mL of deprotected mixture (95% TFA/2.5% TIS/2.5% H)₂O/2.5% EDT) to remove all protecting groups, and this reaction was continued at room temperature (15 to 25 ℃) for 2 hours with continuous stirring. The peptide was then precipitated with cold tert-butyl methyl ether (150mL) and centrifuged (3 min at 3000 rpm). The precipitate was collected and washed two more times with cold tert-butyl methyl ether (150mL each) and the resulting crude peptide was then dried in vacuo for 2 hours. The deprotected peptide exposes two Cys, which are designed to form a first disulfide bond by free oxidation. Thus, the crude peptide is then dissolved in ACN/H₂To O (300mL), 1M NaHCO was added₃Until the pH reached 8 and finally the resulting solution was stirred with make-up air for 16 hours. LCMS indicated formation of the first disulfide bond, and then the solution was lyophilized to dryness. The residue was directly purified by preparative HPLC (TFA conditions) to give compound 5(150mg, 13.7% yield) as a white solid.

Dissolve Compound 5(150mg) in ACN/H₂O (50.0mL), and then 1M HCl was added to adjust the pH to 1, then 0.1M I was added dropwise₂AcOH until the mixture turns brown. The mixture was then stirred at 20 ℃ for 10 hours. LCMS showed reaction completion. The mixture was purified by preparative HPLC (TFA conditions) to give compound 6(70mg, 49.0% yield) as a white solid.

Compound 6(70.0mg, 1.0eq) and BCN-NHS (7.50mg, 1.1eq) were dissolved in DMF (3.00mL) and DIEA (6.00eq) was added slowly. The mixture was stirred at 30 ℃ for 8 hours. LCMS indicated the coupling reaction was complete. In addition, DMF with 20% piperidine was added for Fmoc removal (30 min). The mixture was directly purified by preparative HPLC, and compound 7(20.0mg) was obtained as a white solid.

A mixture of compound 7(20.0mg, 1.0eq) and compound 75(13.6mg, 1.0eq) was dissolved in DMF (1.0mL) and the mixture was stirred at 15 ℃ for 8 h. When the click reaction was complete, the mixture was purified by preparative HPLC. Fractions with the desired m/z (e.g., 1644.9, 1234.2, 987.6, 823.2, etc.) were lyophilized to give I-24 as a white solid (18.1mg, 53.9% yield, 98.3% purity). And (3) purification conditions:

Exemplary preparation of I-25, I-26, I-28 and I-29.

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.3mmol, 0.30g, 1.0mmol/g) and Fmoc-Thr (tBu) -OH (0.119g, 0.30mmol, 1.00eq) in DCM (5mL) and at 15 ℃ under N₂Mix for 2 hours with bubbling. MeOH (0.3mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Trt) -OH (3.00eq), HBTU (2.85eq) in DMF (5mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. Monitoring the coupling reaction by ninhydrin tests, e.g.If it appears colorless, then the coupling is complete. If it shows a blue or reddish-brown color, the coupling is repeated and then checked again with the ninhydrin test until completion. The resin was then washed with DMF (10mL) × 5.

3) Deprotection: DMF (10mL) containing 20% piperidine was added to the resin and the mixture was taken up with N at 15 deg.C₂Bubbling for 30 minutes. The resin was then washed with DMF (10mL) × 5. The deprotection reaction is monitored by the ninhydrin test and is complete if it shows a blue or brownish red colour.

4) Repeating steps 2 and 3 for all other amino acids: see below.

5) After completion of the last position, the resin was washed with DMF (10mL) × 5, MeOH (10mL) × 5 and then dried in vacuo.

Peptide cleavage and purification:

1) to a flask containing the side chain protected peptide was added lysis buffer (92.5% TFA/2.5% TIS/2.5% H) at room temperature₂O/2.5% 3-mercaptopropionic acid) and stirred for 1 hour.

2) Filtered and the filtrate collected.

3) The peptide was precipitated with cold isopropyl ether (100mL) and centrifuged (3 min at 3000 rpm).

4) The precipitate was washed two more times with cold isopropyl ether and the crude peptide was dried under vacuum for 2 hours.

5) To the crude material in ACN/H₂To the mixture in O (300mL) NaHCO was added₃To adjust the pH to 8, and then the mixture was stirred at 15 ℃ for 30 minutes. The mixture was quenched with 1M HCl to adjust the pH to 7. The mixture was dried via lyophilization and the residue was directly purified by preparative HPLC (TFA conditions) to give compound 2(50mg, 90% purity).

To compound 2(50mg, 10.5. mu. mmol, 1.0eq) in MeCN/H₂To a mixture in O (1/1, 3mL) was added TCEP (12.0mg, 42.0. mu. mol, 4.0eq) with saturated NaHCO₃The aqueous solution was basified to pH 8 and the mixture was stirred at 15 ℃ for 3 hours. The mixture was directly purified by Flash (acidic conditions, TFA) to give compound 3(30mg) as a white solid.

Compound 3(25mg, 5.48. mu. mol, 1.0eq) was dissolved in ACN (10mL) and H at 20 deg.C₂O (10 mL). And then by NaHCO₃The pH was adjusted to 8. The mixture was stirred at 20 ℃ for 72 hours. LCMS showed reaction completion. The solution was directly purified by preparative HPLC (TFA conditions) to give I-28 as a white solid (5.0mg, 18.97% yield, 94.8% purity). And (3) purification conditions:

i-25, I-26 and I-29 were prepared in a similar manner. Some results from some preparations are provided below:

compound (I)	LC/MS (+ ESI; main peak)	Purity (HPLC)
			I-25	1491.2	95％
I-26	1461.7	96％
			I-28	1520.5	95％
I-29	1432.4	95％

Exemplary preparation of I-27.

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.5mmol, 0.50g, 1.0mmol/g) and Fmoc-Thr (tBu) -OH (0.198g, 0.50mmol, 1.00eq) in DCM (5mL) and at 15 ℃ under N ₂Mix for 2 hours with bubbling. MeOH (0.5mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Trt) -OH (3.00eq), HBTU (2.85eq) in DMF (5mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. By ninhydrin assayAn attempt was made to monitor the coupling reaction and if it appeared colorless, the coupling was complete. If it shows a blue or reddish-brown color, the coupling is repeated and then checked again with the ninhydrin test until completion. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: see below.

Peptide cleavage and purification:

1) to a flask containing the side chain protected peptide was added lysis buffer (95% TFA/2.5% TIS/2.5% H) at room temperature₂O, 10mL) and stirred for 1 hour.

2) Filtered and the filtrate collected.

3) The peptide was precipitated with cold isopropyl ether (50mL) and centrifuged (3 min at 3000 rpm).

4) Two more washes with isopropyl ether were performed, and the crude peptide was dried under vacuum for 2 hours.

5) Compound 1(800mg, crude material) was obtained as a white solid.

To compound 1 in MeCN/H₂To the mixture in O (500mL) was added 0.1M I dropwise₂AcOH until a pale yellow color remained, and the mixture was stirred at 15 ℃ for 5 minutes. With 0.1M Na₂S₂O₃The mixture was quenched dropwise until the pale yellow color disappeared. The mixture was dried via lyophilization. The residue was directly purified by preparative HPLC (TFA conditions) to give compound 2(200mg, 90.0% purity, 18.2% yield).

Another exemplary peptide synthesis. Peptides were synthesized using standard Fmoc chemistry, for example:

1) preparing resin: to a mixture containing CTC-containing resin (1.0mmol, 1.0g, 1.0mmol/g) and Fmoc-PEG₁₀-CH₂CH₂DIEA (4.00eq) was added dropwise to a container of COOH (0.75g, 1.0mmol, 1.00eq) in DCM (10mL) and N at 15 deg.C ₂Mix for 2 hours with bubbling. MeOH (1.0mL) was then added and the reaction solution was quenched with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (20mL) × 5. DMF (20mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (20mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Mmt) -OH (2.00eq), HBTU (1.90eq) in DMF (5mL) was added to the resin with bubbling. DIEA (4.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it shows a blue or reddish-brown color, the coupling is repeated and then checked again with the ninhydrin test until completion. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: see below.

5) Coupling of the last position: a solution of 2-bromoacetic acid (4.00eq) and DIC (4.00eq) was added to the resin and the mixture was taken up with N₂Bubbling for 20 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. The resin was then washed with DMF (10mL) by 5, MeOH (10mL) by 5 and then dried in vacuo.

Peptide cleavage and purification:

1) to a flask containing the side chain protected peptide was added lysis buffer (2% TFA/2% TIS/96% DCM, 100mL) at room temperature with N₂Bubbling for 20 minutes.

2) Filtered and the filtrate collected. The clear solution was lysis buffer (100mL) containing compound 3(1.0mmol) and was used directly in the next step.

Compound 3(1.0mmol, 100mL in lysis buffer) was diluted with MeOH (1000mL), basified with TEA under an atmosphere of N2 to pH 8, then stirred at 15 ℃ for 2 hours. The solvent was removed under reduced pressure and the residue wet-milled in 0.1M HCl (cold, 100 mL). After filtration, the solid is treated with H₂O (50mL) was washed and then stirred in isopropyl ether (50mL) for 10 min. Finally, the solid was dried under reduced pressure to give compound 4(1.80g, crude material).

A mixture of compound 4(1.80g, 0.63mmol, 1.00eq), compound 4a (522mg, 3.15mmol, 5.00eq), EDCI (361mg, 1.89mmol, 3.00eq) in DMF (10mL) was stirred at 15 ℃ for 3 h. The mixture was added to 0.5M HCl (cold, 100mL) and a large amount of white solid appeared. After filtration, the solid is treated with H ₂O (20mL) was washed and dried via lyophilization to give compound 5(2.0g, crude material) as a white solid.

A mixture of compound 5(2.0g, crude material) was dissolved in a solution containing TFA (45.6g, 400mmol, 30mL), H₂O (0.75g, 41.6mmol, 0.75mL) and triisopropylsilane (0.58g, 3.67mmol, 0.75mL), and stirred at 15 ℃ for 1 hour. The mixture was precipitated with cold isopropyl ether (100mL) and centrifuged (3 min at 3000 rpm). The precipitate was washed two more times with cold isopropyl ether (50 mL). The crude peptide was dried in vacuo for 2 hours and then passed through flash C18: (

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O gradient, 75mL/min) gave compound 6(180mg, 77.4 μmol, 11.5% yield, 90.0% purity) as a white solid.

A mixture of compound 6(80.0mg, 34.4. mu. mol, 1.00eq), compound 2(75.0mg, 34.4. mu. mol, 1.00eq), DIEA (35.5mg, 275. mu. mol, 47.9. mu.L, 8.00eq) in DMF (0.5mL) was stirred at 15 ℃ for 1 hour. The solution was directly purified by preparative HPLC (TFA conditions) to give compound I-27(67.0mg, 15.3 μmol, 44.4% yield, 95.3% purity) as a white solid. LCMS: 1451.6(+ ESI scan; main peak).

And (3) purification conditions:

exemplary preparation of I-30 and I-31.

1) preparing resin: into a vessel containing Rink amide MBHA resin (0.2mmol, 0.65g, 0.31mmol/g) in DMF (5mL) at 15 deg.C with N₂Bubbling for 30 minutes. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Thr (tBu) -OH (3.00eq), HBTU (2.85eq) in DMF (5mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it appears blue or reddish-brown, the coupling is repeated and checked again with ninhydrin test until complete. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: see below.

After cycle 27, the Fmoc group remained on the resin, and then the Mmt group on the Cys side chain was removed by 2% TFA/2% TIS/DCM (2min × 5), and then a disulfide bond was formed on the resin by adding 2eq NCS and allowing to react for 15 min. Disulfide formation was confirmed by pilot cleavage and LCMS analysis, and then Fmoc was removed and 2-bromoacetic acid was coupled as the last residue.

Peptide cleavage and purification:

1) to a flask containing the side chain protected peptide was added lysis buffer (92.5% TFA/2.5% TIS/2.5% H) at room temperature₂O/2.5% 3-mercaptopropionic acid, 10mL) and stirred for 2 hours.

2) Filtered and the filtrate collected.

4) The precipitate was washed twice more with isopropyl ether and the crude peptide was dried under vacuum for 2 hours to give the crude peptide as a white solid (0.68g, crude material).

5) Crude peptide (0.68g) was dissolved in MeCN/H₂O (200mL), then 0.2M NaHCO ₃The pH was adjusted to 8 and stirred at 15 ℃ for 1 hour. After the reaction was complete, the pH of the mixture was adjusted to 6 by 1M HCl. The mixture was dried by lyophilization. By preparative HPLC (acid)Sexual conditions, TFA) to afford compound 425(6mg, 0.89% yield, 96.6% purity) as a white solid.

And (3) purification conditions:

i-31 was prepared in a similar manner. Some results from some preparations are provided below:

compound (I)	LC/MS (+ ESI; main peak)	Purity (HPLC)
			I-30	1088.3	91％
I-31	1113.4	95％

Exemplary preparation of I-32.

The preparation of I-32 is described below as an example.

A mixture of compound 1a (1g, 5.49mmol, 1eq), compound 1(1.50g, 3.53mmol, 0.6eq), TEA (1.11g, 10.98mmol, 1.53mL, 2eq) in EtOH (20mL) was stirred at 90 ℃ for 16 h. The solvent was removed under reduced pressure. The residue was diluted with DCM (100mL), washed with 1M HCl (20mL), and dried over anhydrous Na₂SO₄Drying and concentration under reduced pressure gave compound 2 as a brown oil (2.5g, 4.25mmol, 77.3% yield).

Compound 2(2.5g, 4.25mmol, 1eq) in TFA (10mL) and DCM (10mL) was stirred at 15 ℃ for 0.5 h. The solvent was removed under reduced pressure. By FLASH C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O ether gradient, 75mL/min) to afford compound 3 as a brown oil (1.8g, 2.99mmol, 70.3% yield, TFA).

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (2.0mmol, 2.0g, 1.0mmol/g) and Fmoc-Lys (Boc) -OH (936mg, 2.0mmol, 1.00eq) in DCM (20mL) and was added N at 15 deg.C₂Mix for 2 hours with bubbling. MeOH (2mL) was then added and washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (40mL) × 5. DMF (40mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (20mL) 5 and then proceeded to the next stepAnd (5) carrying out a step.

2) Coupling: a mixture of tert-butyl 3- (2- (2-aminoethoxy) ethoxy) propionate (2.00eq), CDI (2.0eq) in DMF (5mL) was stirred at 15 ℃ for 1 hour. The resulting mixture and DMAP (0.4eq) were then added to the resin with N at 15 deg.C₂Bubbling for 72 hours. The coupling reaction was monitored by ninhydrin test and it appeared colorless, indicating that the coupling was complete. The resin was then washed with DMF (20mL) × 5, MeOH (20mL) × 5 and then dried in vacuo.

Numbering	Material	Coupling reagent
			1	Fmoc-Lys(Boc)-OH(1.00eq)	DIEA(4.00eq)
2	3- (2- (2-Aminoethoxy) ethoxy) propionic acid tert-butyl ester (2.00eq)	CDI(2.00eq)，DMAP(0.4eq)

Peptide cleavage and purification:

1) To the flask containing the side chain protected peptide was added lysis buffer (20% HFIP/DCM, 40mL) at room temperature and stirred twice for 30 min.

2) Filtered and the filtrate collected.

3) The combined filtrates were concentrated under reduced pressure.

4) By Flash C18 (neutral condition, H)₂O/MeCN) to give a colorless oilCompound 5(500mg, crude material).

A mixture of compound 3(519mg, 1.06mmol, 1.07eq), compound 5(0.5g, 988. mu. mol, 1.0eq), DIEA (383mg, 2.97mmol, 516.76. mu.L, 3.0eq), HBTU (375mg, 988. mu. mol, 1.0eq) in DMF (20mL) was stirred at 15 ℃ for 1 hour. By FLASH C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O ether gradient, 75mL/min) to afford compound 6 as a colorless oil (0.6g, 614.63 μmol, 62.15% yield).

Compound 6(0.6g, 614 μmol, 1eq) was dissolved in TFA (6mL) and DCM (6mL) and stirred at 15 ℃ for 0.5 h. The solvent was removed under reduced pressure. By FLASH C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O ether gradient, 75mL/min) to give compound 7 as a colorless oil (500mg, 535 μmol, 87.1% yield, TFA salt).

A mixture of compound 7(500mg, 535. mu. mol, 1.0eq, TFA), Fmoc-OSu (189mg, 562. mu. mol, 1.05eq), DIEA (207mg, 1.61mmol, 279. mu.L, 3.0eq) in DMF (5mL) was stirred at 15 ℃ for 1 h. By FLASH C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O ether gradient, 75mL/min) to give compound 8 as a white solid (350mg, 335 μmol, 62.7% yield).

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.4mmol, 0.4g, 1.0mmol/g, 1.2eq) and Compound 8(350mg, 335. mu. mol, 1.0eq) in DCM (3mL) and was treated at 15 ℃ under N₂Mix for 2 hours with bubbling. MeOH (0.3mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Glu-OtBu (3.00eq), HBTU (2.85eq) in DMF (5mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it appears blue or reddish-brown, the coupling is repeated and checked again with ninhydrin test until complete. The resin was then washed with DMF (10mL) × 5.

3) Deprotection of Fmoc: DMF (10mL) containing 20% piperidine was added to the resin and the mixture was taken up with N at 15 deg.C₂Bubbling for 30 minutes. The resin was then washed with DMF (10mL) × 5. The deprotection reaction is monitored by the ninhydrin test and is complete if it shows a blue or brownish red colour.

4) Repeating step 2 for the next amino acid: (No. 3, 16- (tert-butoxy) -16-oxohexadecanoic acid in Table 2).

5) Deprotection of Dde: will contain 3% of N₂H₄.H₂DMF of O (10mL) was added to the resin and the mixture was taken up with N at 15 deg.C₂Bubbling for 30 minutes. The resin was then washed with DMF (10mL) × 5. The deprotection reaction was monitored by ninhydrin test and it showed blue or reddish-brown indicating that the reaction was complete.

6) Repeating steps 2 and 3 for all other amino acids: see below.

7) Last one isCoupling of individual positions: a solution of 2-bromoacetic acid (4.00eq) and DIC (4.00eq) was added to the resin and the mixture was taken up with N₂Bubbling for 20 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. The resin was then washed with DMF (10mL) by 5, MeOH (10mL) by 5 and then dried in vacuo.

Numbering	Material	Coupling reagent
			1	Compound 8(1.0eq)	DIEA(4.0eq)
2	Fmoc-Glu-OtBu(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			3	16- (tert-butoxy) -16-oxohexadecanoic acid (2.0eq)	HATU (1.90eq) and DIEA (4.0eq)
4	Fmoc-Cys(Mmt)-OH(2.0eq)	HATU (1.90eq) and DIEA (4.0eq)
			5	Fmoc-Asp(OtBu)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
6	Fmoc-HomNle-OH(2.0eq)	HATU (1.90eq) and DIEA (4.0eq)
			7	Fmoc-Bip-OH(2.0eq)	HATU (1.90eq) and DIEA (4.0eq)
8	Fmoc-Leu-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			9	Fmoc-Val-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
10	Fmoc-Gly-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			11	Fmoc-Asp(OtBu)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
13	Fmoc-His(Trt)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			13	Fmoc-Tyr(tBu)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
14	Fmoc-HomNle-OH(2.0eq)	HATU (1.90eq) and DIEA (4.0eq)
			15	Fmoc-Arg(Pbf)-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
16	Fmoc-Ala-OH(3.0eq)	HBTU (2.85eq) and DIEA (6.0eq)
			17	2-Bromoacetic acid (4.0eq)	DIC(2.0eq)

Peptide cleavage and purification:

1) to a flask containing the side chain protected peptide was added lysis buffer (2% TFA/2% Tis/96% DCM, 40mL) at room temperature with N₂Bubbling for 20 minutes.

2) Filtered and the filtrate collected. The clear solution was lysis buffer (400mL) containing compound 10(335 μmol) and was used directly in the next step.

Compound 10 (335. mu. mol, 400mL in lysis buffer) was diluted with MeOH (400mL) in N₂Basified with TEA under atmosphere to pH 8 and then stirred at 15 ℃ for 2 h. The solvent was removed under reduced pressure and the residue wet-milled in 0.1M HCl (cold, 100 mL). After filtration, the solid is treated with H₂O (50mL) was washed and then stirred in isopropyl ether (50mL) for 10 min. Finally, the solid was dried under reduced pressure to give compound 11(1.0g, crude material).

Mixing Compound 11(650mg, 186. mu. mol, 1.0eq), 2, 3, 5, 6-tetrafluorophenol (155mg, 934. mu. mol, 5.0eq), EDCI (107mg, 560. mu. mol, 3.0eq) in DMF (6mL)The mixture was stirred at 15 ℃ for 3 hours. The mixture was added to 0.5M HCl (cold, 50mL), filtered, and the solid was washed with H₂O (cold, 50mL), isopropyl ether (50mL) were washed, dried via lyophilization to give compound 12(700mg, crude material) as a white solid.

With TFA (15.40g, 135mmol, 10mL), H₂A deprotected mixture of O (250mg, 13.88mmol, 0.25mL) and triisopropylsilane (192.75mg, 1.22mmol, 0.25mL) treated Compound 12(600mg, 165. mu. mol) and stirred at 15 ℃ for 1 h. The mixture was precipitated with cold isopropyl ether (50mL) and centrifuged (3 min at 3000 rpm). Two more washes (50mL) were performed with isopropyl ether. The crude peptide was dried in vacuo for 2 hours. The solution was directly purified by preparative HPLC (TFA conditions) to give compound 13(25mg, 8.60 μmol, 5.2% yield) as a white solid.

Peptides were synthesized using standard Fmoc chemistry, for example:

1) preparing resin: into a vessel containing Rink amide MBHA resin (0.2mmol, 0.65g, 0.31mmol/g) in DMF (5mL) at 15 deg.C with N ₂Bubbling for 30 minutes. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Thr (tBu) -OH (3.00eq), HBTU (2.85eq) in DMF (5mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. The resin was then washed with DMF (10mL) × 5.

3) Deprotection: DMF (10mL) containing 20% piperidine was added to the resin and the mixture was taken up with N at 15 deg.C₂Bubbling for 30 minutes. The resin was then washed with DMF (10mL) × 5. Monitoring by ninhydrin testThe deprotection reaction is detected and if it shows a blue or red-brown colour, the reaction is complete.

4) Repeating steps 2 and 3 for all other amino acids: see below.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(2.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
14	Fmoc-Asp(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)

Peptide cleavage, cyclization and purification:

2) Filtered and the filtrate collected.

4) Washed twice more with isopropyl ether and the crude peptide was dried under vacuum for 2 hours to give compound 14(0.2mmol, crude material).

5) Dissolving Compound 14 in MeCN/H₂O (1: 1, 200mL), and then 0.1M I was added dropwise₂HOAc until it remains pale yellow. After 10 minutes, use 0.1M Na₂S₂O₃The mixture was quenched dropwise until the pale yellow color disappeared. The mixture was dried via lyophilization and the residue was directly purified by preparative HPLC (TFA conditions) to give compound 15(120mg, 90% purity).

A mixture of compound 11(25mg, 8.7. mu. mol, 1.0eq), compound 15(17.4mg, 10.5. mu. mol, 1.2eq), DIEA (11.3mg, 87.7. mu. mol, 15.3. mu.L, 10eq) in DMF (0.2mL) was stirred at 15 ℃ for 1 hour. The solution was directly purified by preparative HPLC (TFA conditions) to give I-32(8.9mg, 1.89 μmol, 21.5% yield, 92% purity) as a white solid. LCMS: 1443.4(+ ESI scan; main peak). And (3) purification conditions:

exemplary preparation of I-38.

The chemical formula is as follows: c₂₁₀H₂₉₅N₄₉O₄₈S₃

3) Deprotection: DMF (10mL) containing 20% piperidine was added to the resin and the mixture was taken up with N at 15 deg.C₂Bubbling for 30 minutes. Tree (R)The lipids were then washed with DMF (10mL) × 5. The deprotection reaction is monitored by the ninhydrin test and is complete if it shows a blue or brownish red colour.

4) Repeating steps 2 and 3 for all other amino acids: see below.

Note that: 3% N₂H₄.H₂O/DMF was used for Dde deprotection.

Peptide cleavage and purification:

2) Filtered and the filtrate collected.

5) To compound 1 in MeCN/H₂To the mixture in O (200mL) was added 0.1M I dropwise₂HOAc until it remains pale yellow, followed by 0.1M Na₂S₂O₃The mixture was quenched dropwise until the pale yellow color disappeared. The mixture was dried via lyophilization. The residue was purified directly by preparative HPLC (TFA conditions) to give compound 2(125mg) as a white solid.

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.5mmol, 0.5g, 1.0mmol/g) and 5- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) pentanoic acid (0.17g, 0.5mmol, 1.00eq) in DCM (5mL) and at 15 ℃ in N₂Mix for 2 hours with bubbling. MeOH (0.5mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (20mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Mmt) -OH (2.00eq), HBTU (1.90eq) in DMF (5mL) was added to the resin with bubbling. DIEA (4.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: see below.

Peptide cleavage and purification:

3) to a flask containing the side chain protected peptide was added lysis buffer (2% TFA/2% Tis/96% DCM, 50mL) at room temperature with N₂Bubbling for 20 minutes.

4) Filtered and the filtrate collected. The clear solution was lysis buffer (50mL) containing compound 3(0.5mmol) and was used directly in the next step.

Compound 3(0.5mmol, 50mL in lysis buffer) was diluted with MeOH (500mL) in N₂Basified with TEA under atmosphere to pH 8 and then stirred at 15 ℃ for 2 h. The solvent was removed under reduced pressure. The residue was wet-milled in 0.1M HCl (cold, 50mL), filtered, and the solid was washed with H₂O (50mL) was washed and then stirred in isopropyl ether (50mL) for 10 min. Finally, the solid was dried under reduced pressure to give compound 4(1.00g, crude material).

A mixture of compound 4(1.00g, 0.41mmol, 1.00eq), compound 4a (340mg, 2.06mmol, 5.00eq), EDCI (236mg, 1.23mmol, 3.00eq) in DMF (6mL) was stirred at 15 ℃ for 3 h. The mixture was added to 0.5M HCl (cold, 60mL) and a large amount of white solid appeared. After filtration, the solid is treated with H ₂O (50mL) was washed and dried via lyophilization to give compound 5(1.1g, crude material) as a white solid.

With TFA (22.8g, 200mmol, 15mL), H₂A solvent mixture of O (0.38g, 20.8mmol, 0.38mL) and triisopropylsilane (0.29g, 1.83mmol, 0.38mL) treated Compound 5(1.1g, crude) and was stirred at 15 deg.C for 1 hour. The mixture was precipitated with cold isopropyl ether (100mL) and centrifuged (3 min at 3000 rpm). The precipitate was washed two more times with cold isopropyl ether (50 mL). The crude peptide was dried in vacuo for 2 hours. By FLASH C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O gradient, 75mL/min) gave compound 6(90mg, 47.0 μmol, 11.0% yield, 90.0% purity) as a white solid.

A mixture of Compound 6(40.0mg, 20.9. mu. mol, 1.00eq), Compound 2(43.8mg, 16.73. mu. mol, 0.80eq), DIEA (21.6mg, 167. mu. mol, 29.1. mu.L, 8.00eq) in DMF (0.5mL) was stirred at 15 ℃ for 1 hour. The solution was directly purified by preparative HPLC (acidic conditions, TFA) to give Compound I-38 (Q1: 46.3mg, 10.2. mu. mol, 96.3% purity) and Compound I-38 (Q2: 20.9mg, 4.6. mu. mol, 85.4% purity) as white solids. LCMS: 874.9(+ ESI scans; main peaks; also 1457.6, 1093.3, 729.5, etc.).

And (3) purification conditions:

exemplary preparation of I-39.

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.5mmol, 0.50g, 1.0mmol/g) and Fmoc-Thr (tBu) -OH (0.198g, 0.50mmol, 1.00eq) in DCM (5mL) and at 15 ℃ under N₂Mix for 2 hours with bubbling. MeOH (0.5mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Trt) -OH (3.00eq), HBTU (2.85eq) in DMF (5mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it appears blue or reddish-brown, the coupling is repeated and checked again with ninhydrin test until complete. The resin was then washed with DMF (10mL) × 5.

3) Deprotection: DMF (10mL) containing 20% piperidine was added to the resin and the mixture was mixed at 15 deg.C N for things₂Bubbling for 30 minutes. The resin was then washed with DMF (10mL) × 5. The deprotection reaction is monitored by the ninhydrin test and is complete if it shows a blue or brownish red colour.

4) Repeating steps 2 and 3 for all other amino acids: see below.

5) Urea at the last position: a mixture of Boc-NH2-NH2(6.00eq), CDI (6.00eq) and TEA (6.00eq) in DMF (5mL) was stirred at 15 ℃ for 1 hour. The mixture and DMAP (6.00eq) were then added to the resin with N₂Bubbling for 48 hours. The reaction was monitored by ninhydrin test and if it showed no colour, the coupling was complete. The resin was then washed with DMF (10mL) by 5, MeOH (10mL) by 5 and then dried in vacuo.

Peptide cleavage, cyclization and purification:

2) Filtered and the filtrate collected.

5) Dissolving Compound 1 in MeCN/H₂O (500mL), and then 0.1M I was added dropwise ₂HOAc until it remains pale yellow. After 10 minutes, use 0.1M Na₂S₂O₃The mixture was quenched dropwise until the pale yellow color disappeared. The mixture was then dried via lyophilization. Finally, the residue was directly purified by preparative HPLC (acidic conditions, TFA) to give compound 2(65mg, 90% purity).

1) preparing resin: to a mixture containing CTC-containing resin (1.0mmol, 1.0g, 1.0mmol/g) and Fmoc-PEG₁₀-CH₂CH₂DIEA (4.00eq) was added dropwise to a container of COOH (0.75g, 1.0mmol, 1.00eq) in DCM (10mL) and N at 15 deg.C₂Mix for 2 hours with bubbling. MeOH (1.0mL) was then added and the reaction solution was quenched with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (20mL) × 5. DMF (20mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (20mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Mmt) -OH (2.00eq), HBTU (1.90eq) in DMF (5mL) was added to the resin with bubbling. DIEA (4.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it appears blue or reddish-brown, the coupling is repeated and checked again with ninhydrin test until complete. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: (2 to 14 in Table 2).

Peptide cleavage and purification:

2) Filtered and the filtrate collected. The clear solution was lysis buffer (100mL) containing compound 4(1.0mmol) and was used directly in the next step.

Compound 4(1.0mmol, 100mL in lysis buffer) was diluted with MeOH (1000mL), basified with TEA under an atmosphere of N2 to pH 8, then stirred at 15 ℃ for 2 hours. The solvent was removed under reduced pressure and the residue wet-milled in 0.1M HCl (cold, 100 mL). After filtration, the solid is treated with H ₂O (50mL) was washed and then stirred in isopropyl ether (50mL) for 10 min. Finally, the solid was dried under reduced pressure to give compound 5(1.80g, crude material).

A mixture of compound 5(1.80g, 0.63mmol, 1.00eq), compound 4a (522mg, 3.15mmol, 5.00eq), EDCI (361mg, 1.89mmol, 3.00eq) in DMF (10mL) was stirred at 15 ℃ for 3 h. The mixture was added to 0.5M HCl (cold, 100mL) and a large amount of white solid appeared. After filtration, the solid is treated with H₂O (20mL) was washed and dried via lyophilization to give compound 6(2.0g, crude material) as a white solid.

Compound 6(2g, crude material) in TFA (45.6g, 400mmol, 30mL), H₂A mixture of O (0.75g, 41.6mmol, 0.75mL) and triisopropylsilane (0.58g, 3.67mmol, 0.75mL) was stirred at 15 ℃ for 1 hour. The mixture was precipitated with cold isopropyl ether (100mL) and centrifuged (3 min at 3000 rpm). Two more washes (50mL) were performed with isopropyl ether. The crude peptide was dried in vacuo for 2 hours. By fast C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O gradient, 75mL/min) gave compound 7(180mg, 77.4 μmol, 11.5% yield, 90.0% purity) as a white solid.

A mixture of compound 7(47mg, 20.22. mu. mol, 1.00eq), compound 2(40mg, 20.82. mu. mol, 1.0eq), DIEA (20.9mg, 161.7. mu. mol, 28.1. mu.L, 8eq) in DMF (0.2mL) was stirred at 15 ℃ for 30 minutes. The solution was directly purified by preparative HPLC (TFA conditions) to give I-39 (Q1: 3.7mg, 0.83. mu. mol, 4.0% yield, 94% purity) and I-39 (Q2: 9.8mg, 2.19. mu. mol, 10.6% yield, 92% purity) as white solids. LCMS: 1362.2(+ ESI scan; main peak).

And (3) purification conditions:

exemplary preparation of I-40.

1) preparing resin: a vessel containing Rink amide MBHA resin (0.5mmol, 1.61g, 0.31mmol/g) in DMF (10mL) was bubbled with N2 for 30 minutes at 15 ℃. DMF (20mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (20mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Trt) -OH (3.00eq), HBTU (2.85eq) in DMF (10mL) was added to the resin with bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C ₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. The resin was then washed with DMF (20mL) × 5.

3) Deprotection: DMF (20mL) containing 20% piperidine was added to the resin and the mixture was taken up with N at 15 deg.C₂Bubbling for 30 minutes. The resin was then washed with DMF (20mL) × 5. The deprotection reaction is monitored by the ninhydrin test and is complete if it shows a blue or brownish red colour.

4) Repeating steps 2 and 3 for all other amino acids: see below.

5) After completion of the last position, the resin was washed with DMF (20mL) × 5, MeOH (20mL) × 5 and then dried in vacuo.

Peptide cleavage and purification:

1) to a flask containing the side chain protected peptide was added lysis buffer (95% TFA/2.5% TIS/2.5% H) at room temperature₂O, 20mL) and stirred for 1 hour.

2) Filtered and the filtrate collected.

5) To the crude material in ACN/H₂To the mixture in O (300mL) was added 0.1M I dropwise₂AcOH until a pale yellow color remained, and the mixture was stirred at 15 ℃ for 5 minutes. With 0.1M Na ₂S₂O₃The mixture was quenched dropwise until the pale yellow color disappeared. The mixture was dried via lyophilization, and the residue was then directly purified by preparative HPLC (acidic conditions, TFA) to give compound 2(150mg, 90% purity)

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.5mmol, 0.50g, 1.0mmol/g) and Fmoc-Gly-OH (0.149g, 0.50mmol, 1.00eq) in DCM (5mL) and was added N at 15 deg.C₂Mix for 2 hours with bubbling. MeOH (0.5mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5, and then DMF (10mL) with 20% piperidine was added, and the mixture was washed with N at 15 ℃₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. Resin compositionWash with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Mmt) -OH (2.00eq), HBTU (1.90eq) in DMF (5mL) was added to the resin with bubbling. DIEA (4.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it shows a blue or reddish-brown color, the coupling is repeated once more and checked again with ninhydrin test until the coupling is complete. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: (2 to 14 in Table 2).

Peptide cleavage and purification:

2) Filtered and the filtrate collected. The clear solution was lysis buffer containing compound 3(0.5mmol, 100mL) and was used directly in the next step.

3) Compound 3(0.5mmol, 100mL in lysis buffer) was diluted with MeOH (500mL), basified with TEA to pH 8 under N2 atmosphere, and ligated Followed by stirring at 15 ℃ for 4 hours. The solvent was removed under reduced pressure and the residue wet-milled in 0.1M HCl (cold, 100 mL). After filtration, the solid is treated with H₂O (50mL) was washed, and then stirred in isopropyl ether (50mL) for 10 minutes, and finally dried under reduced pressure to give compound 4(1.2g, crude material).

A mixture of compound 4(1.2g, 1.00eq), compound 4a (501mg, 6.00eq), EDCI (288mg, 3.00eq) in DMF (10mL) was stirred at 15 ℃ for 3 hours. The mixture was then added to 0.5M HCl (cold, 100mL) and a large amount of white solid appeared. After filtration, the solid is treated with H₂O (20mL) was washed and dried via lyophilization to give compound 5(1.8g, crude material) as a white solid. Deprotection mixture (95% TFA/2.5% TIS/2.5% H)₂O, 30mL) was treated with the crude material for 1.5 hours. The mixture was precipitated with cold isopropyl ether (100mL) and centrifuged (3 min at 3000 rpm). The precipitate was washed two more times with cold isopropyl ether (50 mL). The crude peptide was dried in vacuo for 2 hours. By fast C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O gradient, 75mL/min) the residue was purified directly to give compound 6(55mg) as a white solid.

A mixture of compound 6(55mg, 1.00eq), compound 2(51.3mg, 1.10eq), DIEA (30.7. mu.L, 6.00eq) in DMF (0.5mL) was stirred at 15 ℃ for 1 hour. The solution was directly purified by preparative HPLC (TFA conditions) to give compound 523(15.4mg, 15.9% yield, 98.6% purity) as a white solid. LCMS: 1098.4(+ ESI scan; main peak).

And (3) purification conditions:

exemplary preparation of I-33, I-34, I-35, I-36, I-37, I-41 and I-42.

1) preparing resin: DIEA (4.00eq) was added dropwise to a vessel containing CTC resin (0.5mmol, 0.50g, 1.0mmol/g, 1.00eq) and Fmoc-Thr (tBu) -OH (0.158g, 0.40mmol, 0.8eq) in DCM (5mL) and at 15 ℃ under N₂Mix for 2 hours with bubbling. MeOH (0.5mL) was then added and the reaction solution was washed with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: a solution of Fmoc-Cys (Trt) -OH (877mg, 1.5mmol, 3.00eq), HBTU (541mg, 1.42mmol, 2.85eq) in DMF (5mL) was added to the resin with N2 bubbling. DIEA (6.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it appears blue or reddish-brown, the coupling is repeated and checked again with ninhydrin test until complete. The resin was then washed with DMF (10mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: see below.

Numbering	Material	Coupling reagent
			1	Fmoc-Thr(tBu)-OH(0.80eq)	DIEA(4.00eq)
2	Fmoc-Cys(Trt)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			3	Fmoc-Trp(Boc)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
4	Fmoc-Val-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			5	Fmoc-Leu-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
6	Fmoc-Glu(OtBu)-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
			7	Fmoc-Gly-OH(3.00eq)	HBTU (2.85eq) and DIEA (6.00eq)
8	Fmoc-Leu-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			9	Fmoc-His(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
10	Fmoc-Trp(Boc)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			11	Fmoc-Ala-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
12	Fmoc-Cys(Trt)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
			13	Fmoc-Asp(OtBu)-OH(3.00eq)	HATU (2.85eq) and DIEA (6.00eq)
14	Fmoc-PEG8-CH2CH2COOH(2.00eq)	HATU (1.90eq) and DIEA (4.00eq)

Peptide cleavage and purification:

1) to the containing side at room temperatureChain protected peptide flasks lysis buffer (95% TFA/2.5% TIS/2.5% H) was added₂O) and stirred for 1 hour.

2) Filtered and the filtrate collected.

5) Compound 5(800mg, crude material) was obtained as a white solid.

Dissolving Compound 1 in MeCN/H₂O (500mL), and 0.1M I was added dropwise₂HOAc until the color of the mixture became light yellow, followed by stirring the mixture at 15 ℃ for 10 minutes. With 0.1M Na₂S₂O₃The mixture was quenched dropwise until the color of the mixture became colorless and dried via lyophilization. The residue was directly purified by preparative HPLC (acidic conditions, TFA) to give compound 2(170mg, 90.0% purity, 17.4% yield).

Peptides were synthesized using standard Fmoc chemistry, for example:

1) preparing resin: to a mixture containing CTC-containing resin (0.62mmol, 0.62g, 1.0mmol/g, 1.25eq) and Fmoc-PEG₈-CH₂CH₂DIEA (4.00eq) was added dropwise to a container of COOH (0.198g, 0.50mmol, 1.00eq) in DCM (10mL) and N at 15 deg.C₂Mix for 2 hours with bubbling. MeOH (1.0mL) was then added and the reaction solution was quenched with N₂Bubbling was continued for another 30 minutes. The resin was washed with DMF (10mL) × 5. DMF (10mL) containing 20% piperidine was then added and the mixture was stirred with N at 15 deg.C₂Bubbling for 30 minutes. The mixture was then filtered to obtain a resin. The resin was washed with DMF (10mL) × 5 before proceeding to the next step.

2) Coupling: in N₂A solution of Fmoc-Cys (Mmt) -OH (615mg, 1.00mmol, 2.00eq), HBTU (360mg, 0.95mmol, 1.90eq) in DMF (10mL) was added to the resin with bubbling. DIEA (4.00eq) was then added dropwise to the mixture and N was used at 15 deg.C₂Bubbling for 30 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. If it appears blue or reddish-brown, the coupling is repeated and checked again with ninhydrin test until complete. The resin was then washed with DMF (20mL) × 5.

4) Repeating steps 2 and 3 for all other amino acids: see below.

5) Coupling of the last position: a solution of 2-bromoacetic acid (4.00eq) and DIC (4.00eq) was added to the resin and the mixture was taken up with N₂Bubbling for 20 minutes. The coupling reaction was monitored by ninhydrin test and if it appeared colorless, the coupling was complete. The resin was then washed with DMF (20mL) × 5, MeOH (20mL) × 5 and then dried in vacuo.

Peptide cleavage and purification:

2) Filtered and the filtrate collected. The clear solution was lysis buffer containing compound 3(1.0mmol, 100mL) and was used directly in the next step.

Compound 3(1.0mmol, 100mL in lysis buffer) was diluted with MeOH (1000mL), basified with TEA under an atmosphere of N2 to pH 8, and then stirred at 15 ℃ for 2 hours. The solvent was removed under reduced pressure and the residue wet-milled in 0.1M HCl (cold, 100 mL). After filtration, the solid is treated with H₂O (50mL) was washed and then stirred in isopropyl ether (50mL) for 10 min. Finally, the solid was dried under reduced pressure to give compound 4(0.75g, crude material).

A mixture of compound 4a (226.2mg, 1.36mmol, 5.00eq), compound 4(0.75g, 272.4. mu. mol, 1.00eq), EDCI (156.71mg, 817.48. mu. mol, 3.00eq) in DMF (5mL) was stirred at 15 ℃ for 3 hours. The mixture was added to 0.5M HCl (cold, 50mL) and a large amount of white solid appeared. After filtration, the solid is treated with H₂O (20mL) was washed and dried via lyophilization to give compound 5(0.80g, crude material) as a white solid.

Compound 5(0.80g, crude material) was dissolved in a solution containing TFA (17.6g, 154.3mmol, 11.4mL), H₂O (285.7mg, 15.8mmol, 285. mu.L) and triisopropylsilane (220.29mg, 1.39mmol, 285.71. mu.L), and the mixture was stirred at 15 ℃ for 1 hour. The mixture was then precipitated with cold isopropyl ether (100mL) and centrifuged (3 minutes at 3000 rpm). The precipitate was washed two more times with cold isopropyl ether (50 mL). The crude peptide was dried in vacuo for 2 hours. By fast C18(

120g

C18 flash column, eluent: 0 to 90% MeCN/H₂O gradient, 75mL/min) gave compound 6(90mg, 40.2 μmol, 14.5% yield, 90.0% purity) as a white solid.

A mixture of compound 6(50mg, 22.3. mu. mol, 1.00eq), compound 2(43.60mg, 22.3. mu. mol, 1.00eq), DIEA (23.1mg, 178.7. mu. mol, 31.1. mu.L, 8.00eq) in DMF (0.5mL) was stirred at 15 ℃ for 1 hour. The solution was directly purified by preparative HPLC (acidic conditions, TFA) to give I-33(33.0mg, 7.71 μmol, 34.4% yield, 93.9% purity) as a white solid.

And (3) purification conditions:

i-34, I-35, I-36, I-37, I-41 and I-42 were prepared in a similar manner. Some results from some preparations are provided below:

Compound (I)	LC/MS (+ ESI; main peak)	Purity (HPLC)
			I-33	1342.7	94％
I-34	1166.6	96％
			I-35	1195.8	97％
I-36	1254.6	97％
			I-37	1313.3	96％
I-41	1366.5	92％
			I-42	1361.6	91％

In many cases, various other compounds, including various ARM agents, are also prepared and evaluated using one or more of the techniques described in the examples.

Example 2 the provided compounds recruit antibodies to target cells.

Various techniques can be used to assess and/or characterize the recruitment of antibodies to target cells (e.g., cancer cells). One such assay is a ternary binding assay. Exemplary schemes are described herein. Compounds were diluted in DMSO (MP 191418) into 1000 x to 96 well polypropylene plates (Corning 3357) at the starting concentration used in the assay. It was then serially diluted in 1/2 log increments to yield 8 to 12 concentrations in DMSO (depending on the assay). These DMSO stocks were then gradually diluted 1/100 into PBS (VWR cat No. 20012043). The stepwise diluted series of compounds was then added to the polypropylene assay plate at 1/10 volumes of the assay volume. Daudi (ATCC CCL-213) (non-adherent cell line) was counted and centrifuged, and resuspended in flow buffer at a concentration of 100,000 cells per 90 microliters: 1% BSA (American Bio) AB 01088-00100; 0.5mM EDTA (VWR 45001-122); PBS labeled with 11.1. mu.g/mL human IgG1K phycoerythrin (southern Biotech accession 0151K-09PE) (VWR catalog No. 20012043). Cells were then added to polypropylene plates containing stepwise diluted compounds and incubated at 37 ℃ for 30 minutes. At the end of incubation, cells were centrifuged and washed 2X with running buffer containing 0.5% Tween 20(BP 337-500). Samples were analyzed on a BD FacsCelesta. Mean fluorescence was analyzed using Graphpad Prism and a curve was fitted using log (inhibitor) and reaction-variable slope (four parameters). As shown in fig. 1, the provided compounds can recruit antibodies to target cells. In one set of experiments, IC50 for I-9 was about 16nM, and IC50 for I-17 was about 2.6 nM. The identity and/or activity of the provided technology is confirmed by assessing additional compounds. For example, various provided compounds can recruit antibodies to target cells, as shown below (MFI at various concentrations):

IC50(nM) from some assessments e.g.:

ID	IC50(nM)	ID	IC50(nM)
				I-9	16	I-34	20
I-17	5.9	I-35	10
				I-25	9.5	I-36	10
I-26	14	I-37	7.1
				I-27	6	I-38	＞3000
I-28	15	I-39	3.3
				I-29	61	I-40	50
I-30	14	I-42	2.2
				I-31	＞3000	I-41	3
I-32	88	I-43	43
				I-33	9.3	I-44	19

effective recruitment of effector cells to various other cell types in the presence of IgG was confirmed by additional analysis.

As described herein, in some embodiments, a provided compound binds to CD38 with a Kd of no more than 200nM, 100nM, 50nM, 40nM, 30nM, 20nM, 10nM, or 5nM as measured by SPR and/or binds to an antibody with a Kd of no more than 200nM, 100nM, 50nM, 40nM, 30nM, 20nM, 10nM, or 5nM as measured by SPR. In some embodiments, compounds provided (e.g., I-9 and I-17) can bind to CD38 with a Kd of about 10nM and to human IgG1 and IgG2 with a Kd of about 10 to 20nM, as shown by SPR. The provided compounds are shown to bind to several IgG isotypes with nanomolar Kd binding affinity.

Example 3. the provided compounds recruit and activate effector cells.

Daudi (ATCC CCL-213) cells were resuspended in Opti-MEM (Thermo Fisher Scientific number 31985070), counted (Life Technologies Countless II cell counter) and seeded (5,000 cells per 25 microliters; corning plate: 3917). Compounds were diluted in DMSO (MP 191418) into 1000 x to 96 well polypropylene plates (corning 3357) of the starting concentration used in the assay. It was then serially diluted in 1/2 log increments to yield 8 concentrations in DMSO (depending on the assay). These DMSO stocks were then gradually diluted 1/250 into Opti-MEM. The stepwise diluted series of compounds were then added to a polypropylene assay plate at 25 μ l/well. The human antibody solution (Grifols IVIG Fleogama No. 61953-0005-2) was diluted to 40. mu.g/mL and added at 25. mu.l/well. Effector cells (ADCC reporter cells, Promega (Promega) kit: G7018) were added at 37,500 cells per 25 microliters of wells. The assay was then incubated at 37 ℃ for 18 hours. After the induction period, the plates were equilibrated to 25 ℃ followed by addition of luciferase substrate (75. mu.l/well, 1 vial in 10mL Bio-Glo assay buffer, Promega kit: G7018). Luminescence was measured (Biotek Synergy H1 microplate reader). Exemplary data from a set of experiments is presented in FIG. 2, where EC50 for I-9 is about 0.92nm and EC50 for I-17 is about 2.7 nm. Various assays, including animal models, confirm the recruitment and activation of various types of effector cells, such as macrophages, NK cells, and the like. As shown, the provided compounds can recruit and activate effector cells. Assessment of additional compounds confirms the nature and/or activity of the provided technology. For example, various provided compounds can recruit and activate effector cells (RLUs at various concentrations):

EC50(nM) from some assessments e.g.:

ID	EC50(nM)	ID	EC50(nM)
				I-9	5.5	I-34	6.7
I-17	5.9	I-35	4.4
				I-25	4.7	I-36	3.4
I-26	2.4	I-37	1.8
				I-27	3	I-38	53
I-28	14	I-39	0.61
				I-29	9.9	I-40	50
I-30	12	I-42	1.4
				I-31	＞3000	I-41	24
I-32	63	I-43	11
				I-33	4.3	I-44	11

example 4. the provided compounds can kill target cells.

In some embodiments, CD38-ABT ARM binds to a target cell and an antibody, e.g., a human antibody. In some embodiments, such a triplet presents an antibody to an effector cell (e.g., an NK cell) and binds to, for example, the CD16a receptor. Experiments were performed in a system similar to physiological systems using purified NK cells from multiple donors with different single nucleotide polymorphic variants of CD16a (V/V, F/F and V/F) to confirm the activity of the provided compounds (e.g., ARM). Daudi cells were transfected with KILR reporter construct (DiscoverX number 97-0002). The attenuated lentiviruses are designed to deliver Moloney Murine Leukemia Virus (MMLV) engineered to drive expression of a housekeeping gene labeled with enhanced ProLabel (ePL) (β -galactosidase (β -gal) reporter fragment). This construct is designed to remain inside the cell. Death results in the release of the KILR reporter protein into the culture medium. The detection reagent (DiscoverX number 97-0001L) contains a complementary beta-gal reporter fragment enzyme receptor (EA). The two components combine to produce a chemiluminescent signal. Data from one set of experiments is presented in FIG. 3, where EC50 for I-9 is 6.7nm and EC50 for I-17 is 5.9 nm. It has been demonstrated that provided agents, as described herein, can recruit effector cells from various sources to kill various target cells expressing CD38 associated with various conditions, disorders or diseases (e.g., cancer, e.g., multiple myeloma), which EC50 is typically in the low micromolar, nanomolar, or low nanomolar range. In some embodiments, the provided compounds can kill multiple myeloma cells in a bone marrow sample of a patient ex vivo as well as leukemia plasma cells in the blood of the patient. In some embodiments, an animal model (e.g., an animal model for burkitt's lymphoma, multiple myeloma, etc.) is utilized to confirm the efficacy of a provided compound. As shown, the provided compounds can be effective to induce killing of target cells, e.g., via recruitment of antibodies and ADCC. The identity and/or activity of the provided technology is confirmed by assessing additional compounds. For example, various provided compounds can provide activity (dead cell%) against a target cell via or including ADCC in various instances:

EC50(nM) from some assessments e.g.:

example 5 the provided compounds did not deplete effector cells expressing CD 38.

In some embodiments, the provided technology provides various advantages over existing CD 38-based technologies (e.g., technologies using CD38 antibodies). Furthermore, the provided technology does not deplete or significantly reduce normal CD 38-expressing cells, such as many immune cells, compared to CD38 antibody-based technologies. As will be appreciated by those skilled in the art, various techniques can be used to assess depletion of effector cells expressing CD 38. In one example, EasySep was used according to manufacturer's instructions^TMHuman NK cell isolation kit (STEMCELL Technologies catalog No. 17955) NK cells are purified from frozen stocks using 3X 10^7PBMC preparations (Stem cell Technologies, Inc.). NK cells were seeded in a volume of 100. mu.L per well in round bottom 96-well plates at a density of 2X 10^6 cells per ml OPTIMEM medium. Daramomum mono antibody was added to a final concentration range of 3. mu.g/mL to 0.1. mu.g/mL. Compound I-9 was added to the cultures at a final concentration range of 300nM to 10 nM. IvIG was used at a final concentration of 10. mu.g/mL. The cells were mixed by pipetting up and down and incubated at 37 ℃ for 18 hours. At the end of the incubation period, the cells were centrifuged at 400g for 5 minutes and resuspended in PBS. Thereafter, cells were stained with 1 μm Zombie viability dye (Biolegged, Cat. No. 423111) according to the manufacturer's instructions and in the chamber Incubate at room temperature for 15 minutes. The fluorescent antibody mixture was then added to cells containing CD56 PE, CD38 PE-Cy7, CD3 BV786, and CD107a BV421 in PBS 1% BSA, 0.5mM EDTA buffer. The cells were further incubated at 4 ℃ for 15 minutes and washed twice with 200. mu.L PBS 1% BSA, 0.5mM EDTA buffer. The cells were resuspended in a final volume of 150. mu.L PBS 1% BSA, 0.5mM EDTA buffer and 20. mu.L of Count Bright^TMAbsolute count beads (seimer feishier catalog No. C36950) to determine absolute cell counts. Cells were analyzed on a BD FACSCelesta flow cytometer (BD Biosciences). NK cells are defined as CD3-CD56⁺. The percentage of Zombie green positive NK cells was analyzed and plotted using GraphPad Prism software. Data from one example is presented in fig. 4. As shown, the provided ARM did not deplete effector cells, e.g., NK cells, expressing CD 38. Various additional analyses, including in vivo animal models, demonstrate that the provided techniques can effectively kill diseased cells (e.g., cancer cells), do not induce NK cell suicide or CDC, and/or do not significantly affect immune cell populations (e.g., various types of immune cells, such as in bone marrow immune cell populations) as compared to CD38 antibodies (e.g., daratumab), demonstrate that the provided techniques can be highly efficient and do not cause significant side effects/toxicity as compared to antibody-based techniques.

Example 6. the provided technology can effectively kill cancer cells without causing significant side effects.

Cancer therapy can have various side effects. For example, therapy with antibodies against certain cancer antigens may harm, inhibit, or kill non-cancer cells that include the same antigen. Furthermore, the present disclosure presents the following results, demonstrating that the provided technology is effective against cancer cells expressing various antigens while having much less side effects/toxicity compared to other technologies (including antibody-based technologies) targeting the same antigen. For example, the provided techniques do not significantly reduce the number of non-cancerous cells expressing the same target as compared to other techniques.

Some applicable procedures

PBMC separation: from the bodyThe leukopheresis products of donors with a quality index (BMI) between 19 and 25, an age of less than 50 years, no immunosuppressive drugs administered for at least 2 weeks, an estimated PBMC cell count > 10^10 were obtained from KeyBiologics (goal ID 20982200) and shipped at ambient temperature. The leukopheresis bag was wiped with 70% EtOH, a small slit was cut, and the contents were pipetted into the test tube. The contents of Leukopak were diluted 1: 1 with PBS without Ca + +/Mg + +, and 20mL of this mixture was layered on top of 25mL Ficoll. The tube was then centrifuged at 400g for 30 minutes without interruption. PBMCs were collected from the interface into separate tubes, and the tubes were filled to 50mL with PBS. Cells were centrifuged at 120g for 10 min to remove platelets. The supernatant was decanted and the cells were resuspended in RPMI 10% FBS at a concentration of 7 to 10X 10^6 cells/ml. Cells were incubated at 37 ℃ with 5% CO ₂Incubate under atmosphere overnight until NK cells detached.

And (3) NK cell separation: PBMC were centrifuged at 400g for 10 min and resuspended in EasySep buffer. NK cells were isolated using NK cell isolation kit from Stem cell technology, Inc according to the kit manufacturer's instructions. NK cell purity and phenotype were assessed by trypan Blue (trypan Blue) and flow cytometry using the following antibody cocktail: anti-CD 56PE, CD3 APC, and viability was determined by staining with trypan blue exclusion dye and by flow cytometry using near-infrared fixable viability dye (seemer feishol).

CIML NK cell production: isolated NK cells were resuspended in XVIVO 10% human serum and IL-15(50ng/ml), IL-12(10ng/ml), IL-18(50ng/ml) at 2X 10^6 cells/ml for 12 to 18 hours. Cells were collected and tested for purity and viability by trypan blue staining and by flow cytometry using near infrared fixable viability dyes (seemer feishel), CD3 APC (bio-legend) and CD56PE (bio-legend).

Treatment with I-17: i-17 was dissolved in DMSO to prepare a 25mM stock solution. The stock was then serially diluted in 100% DMSO to obtain the 1000 × concentration to be used for the experiment. Then 100% DMSO compound stock was added to the tube and the medium was added to a volume of 1000 μ Ι per 1 μ Ι compound and vortexed for 1 minute to ensure a homogeneous mixture. NK cell pellets were resuspended directly in I-17 solution at a cell density of 5X 10^6 cells/ml.

CIML NK cell self phase killing assay: NK cells were resuspended directly in the solutions generated for each concentration of I-17 at a density of 5X 10^6 cells/ml. Similarly, NK cell pellets were resuspended in Darandian single anti-control antibody solution (range of 3. mu.g/ml to 0.01. mu.g/ml in PBS 5% HSA). The resulting NK cell suspension was aliquoted at 55. mu.l per well of 96-well v-bottom plate and at 37 ℃ in 5% CO₂Incubate under atmosphere for 2 hours.

CIML NK cells SUDHL-4 cell ADCC assay: SuDHL-4 cells were labeled with CFSE and resuspended in XVIVO15 medium containing 20% human serum. Cells were aliquoted at 10,000 cells per well, 18 μ Ι per well in a 96 well V-bottom plate. NK cells (in PBS 5% HSA) were added in equal volumes (18. mu.l per well) at a 9: 1 ratio (90,000 NK cells per well). The CO-culture was incubated at 37 ℃ in 5% CO₂Incubate under atmosphere overnight. The following day, cells were washed and stained with the following reagents: near infrared fixable vital dyes (seimenfiel), CD3 FITC (bioglass) and CD56 PE (bioglass). The percentage of dead SUDHL-4 cells was calculated by gating on CFSE + cells that were also positive for near-infrared vital stain.

Some results

Purity and viability of NK cells and CIML NK cells: in addition, the present disclosure provides a population of NK cells with high purity and viability following isolation from PBMCs. Peripheral blood mononuclear cells were isolated to form leukodepleted products, with > 99% PBMC viability after isolation as determined by trypan blue and by flow cytometric analysis. After separation using magnetic bead assisted negative selection, NK cells were 90% pure and more than 99% viable as determined by both trypan blue and flow cytometry. T cell contamination (CD3+ CD 56-cells) in the NK cell fraction was found to be 2.8% on the day of isolation. After isolation of NK cells, they were divided into two treatment groups, CIML NK cells and non-CIML (control cells). CIML NK cells were incubated overnight in XIVO15 medium containing 10% human serum and IL-12, IL-15 and IL-18, while control non-CIML NK cells received no cytokine treatment. After overnight incubation, purity and viability were assessed in the cultured cell populations. In one experiment, the viability of CIML and non-CIML control NK cells determined by trypan blue was 50%. The viability of CIML NK cells determined by flow cytometry was 75%, whereas the viability of control non-CIML NK cells determined by flow cytometry method was 78%. At the time of harvest, T cell contamination in both cultures ranged from 1.2% to 1.8%.

The provided technology exhibits significantly lower toxicity compared to a corresponding technology comprising antibodies directed against the same target.

NK cell suicide (NK cell-directed death in the same culture at NK cells) was assessed by flow cytometry after 2 hours of incubation with the indicated concentration of I-17 in the presence or absence of 500 μ g/ml intravenous immunoglobulin (IVIG). Figure 5 shows the frequency of dead NK cells as a function of I-17 concentration in daratumab, CD 38-directed therapeutic antibody, or culture supernatant.

As shown, the provided techniques exhibit significantly lower toxicity compared to corresponding techniques using antibodies, e.g., when assessed by a reduction in cell number of non-cancer cells. For example, at only 2 hours after incubation, 3 μ g/ml or 20.1nM of daptomu mono-antibody treatment resulted in a 4% increase in the percentage of dead NK cells present in the cultured medium compared to no increase in the case of I-17+/-IVIG for CIML NK cells (FIG. 5). In cultures of non-CIML NK cells, treatment with daptomycin produces a total increase of 5.6% dead NK cells compared to DMSO-treated controls, whereas treatment with the highest concentration of I-17(25 μ M) caused a 1.7% increase (25 μ M of I-17 versus DMSO controls) and a 0.93% increase (I-17 IvIG versus DMSO IVIG controls) in dead NK cells. Figure 5(B) presents data normalized to DMSO-treated controls. As shown, no significant NK cell suicide was detected even at the highest dose of I-17, in sharp contrast to darunavir (a CD38 therapeutic antibody approved by the FDA for the treatment of multiple myeloma).

The provided technology can effectively reduce the number of target cancer cells.

Antibody-dependent cytotoxicity assays were performed to measure the effect of CIML NK cells alone and in combination with I-17 on SUDHL-4 multiple myeloma cells of interest. Baseline activity was assessed by using NK cells that had not been stimulated with cytokine cocktail (non-CIML NK cells). FIG. 6 presents the frequency of dead SUDHL-4 cells in NK-SUDHL-4 cell co-cultures after 18 hours of incubation.

As shown from the data presented in fig. 6B, CIML NK cells are potent killers of SUDHL-4 target cells compared to baseline (DMSO-treated control). Additional target cell killing compared to DMSO-treated control levels can be achieved by CIML NK cells in combination with I-17-an increase in killing of 66% compared to background was observed. Furthermore, as shown herein, the provided techniques can effectively utilize IgG present in human serum, and do not require the administration of additional antibodies, such as exogenous antibodies similar to those used in antibody-based therapies. Data using darunavir targeting CD38 is also included. As demonstrated herein, the provided techniques kill cancer cells efficiently while being less toxic than antibody-based techniques.

Example 7. the provided technology can effectively kill a given cell with low toxicity.

Furthermore, this example demonstrates that the provided techniques can effectively reduce the number of cancer cells. In this example, I-17 (as in the examples above), cytokine-induced memory-like NK cells (CIML NK cells) and optionally intravenous immunoglobulin (IVIG) were utilized. In addition, the present disclosure demonstrates the activity of the provided technology against bone marrow plasma cells in multiple myeloma patients.

Materials, methods and apparatus

Test and control articles

I-17 (25 mM solution in DMSO)

Darlazeux (Darzalex) -Parexel DRE0607

Intravenous IVIG human immunoglobulin, Flebogama-Grifols NDC 61935-

Materials and apparatus

Bovine Serum Albumin (BSA) heat shock, fraction V-American organism AB01088-00100

Phosphate Buffered Saline (PBS) -Gibco 10010, (-) Ca (-) Mg, pH 7.4

Intravenous IVIG human immunoglobulin, Flebogama-Grifols NDC 61935-

biotinylated/His-tagged human CD38 protein, Avi Tag-Popseris (Acro Biosystems) CD8-H82E7

Neutravidin-Invitrogen (31000, 1 mg/ml)

Dimethyl sulfoxide (DMSO), Sigma-Aldrich 276855

Ethylenediaminetetraacetic acid (EDTA) VWR 97062-656

Running buffer-PBS pH 7.4+ 0.05% (w/v) BSA, 2mM EDTA

Assay plate, 96-well V-bottom-VWR corning 3357

Attune NxT flow cytometer and Attune NxT software

96 well 2ml deep well plate, catalogue number 1896-

Ficoll (R) Paque Plus, GE Healthcare group catalog number 17-1440-03

EasySEP^TMHuman NK cell isolation kit, catalog No. 17955 of Stem cell technology Co., Ltd

Premium grade human IL-15, Cat. Ataland Biotech (Miltenyi Biotec) catalog number 130-

Premium grade human IL-12, catalog number 130-

Human IL-18, Andi Biopsis (R & D Systems) catalog number 9124-IL-010

Special cell culture medium, Lonza X-VIVO15, Saimer Feishell scientific catalog number BW04-744Q

Human AB blood clot serum, Gemini Bioproducts catalog number 100-

Albumin from human serum, Sigma-Aldrich catalog A5843-5G

RBC lysis buffer 10X (Tonbo Biosciences catalog number TNB-4300-L100)

Minimal residual disease antibody staining group:

Antigens	Fluorophores	Cloning	Suppliers of goods	Directory number
					CD138	BV421	MI15	Biological science of BD	562935
CD27	BV510	O323	Biographical legends	302835
					CD38ME	FITC	Multi-epitope	Cytognos	CYT-38F2
CD56	PE	5.1H111	Biographical legends	362508
					CD45	PERCPCY5.5	HI30	Biographical legends	304028
CD19	PECY7	HIB19	Biographical legends	302216
					CD117	APC	104D2	BD	341096

Patient bone marrow and blood were obtained from Discovery Life Sciences (Discovery Life Sciences).

Scheme(s)

Bone marrow (3ml) and blood (20ml) from patients found in Biosciences (Discovery Biosciences) were transported at ambient temperature. Bone marrow was diluted 1: 1 with PBS and 50^ l of bone marrow-PBS mixture was aliquoted into 96-deep well plates. Bone marrow cells were incubated overnight until the next day CIML cells were added.

PBMCs were isolated from blood by Ficoll density gradient centrifugation. PBMC were centrifuged at 400g for 10 min and resuspended in EasySep buffer. NK cells were isolated using NK cell isolation kit from Stem cell technology, Inc according to the kit manufacturer's instructions.

NK cells were cultured at 1X 10⁶Each cell/ml was resuspended in XVIVO15, 10% human serum, IL-15(50ng/ml), IL-12(10ng/ml), IL-18(50ng/ml) and incubated for 18 hours. After overnight incubation with cytokines, NK cells were washed twice with PBS 5% human serum albumin, counted and cultured at 2 × 10 per ml XVIVO15 medium ⁵Cell density of individual cells was resuspended. To a cell containing 50^ l bone marrow: twenty microliters (4000 cells) was added to each well of the PBS mixture. Mixing dacematoclone antibody (3^ g/ml [20 nM)]To 0.3^ g/ml [2nM]) And I-17(25^ M to 3^ M final concentration) was made 10X of the final concentration to be used for analysis, and 8^ l of I-17 or 7^ l of Darasba monocarb 10X stock solution was added to the relevant well. To I-17 treated wells, human IVIG was added to a final concentration of 10^ g/ml. Control wells received XVIVO15 medium. The well contents were mixed by pipetting up and down and the plate was centrifuged at 400g for 1 minute.

Then at 37^ C, 5% CO₂The lower incubation was analyzed for 4 hours. After incubation, 1ml of 1 × erythrocyte lysis buffer was added to each well and the cells were incubated at room temperature for 15 minutes. Plates were centrifuged at 400g for 3 minutes and another round of erythrocyte lysis and centrifugation was performed. The cells were then resuspended in 200^1 FACS buffer and centrifuged. The buffer was discarded and the cells were resuspended in 100^1 fluorescent antibody mixture. The cells were incubated at 4^ C for 15 minutes, 200^1 FACS buffer was added to each well for washing, the cells were centrifuged at 400g for 3 minutes, and the supernatant was discarded. The washing was repeated 2 more times. Finally, the cells were resuspended in 200^1 FACS buffer and analyzed using an Attune flow cytometer. Data were analyzed using FlowJo software and graphed using GraphPad Prism.

The provided techniques reduce the number of plasma cells.

FIG. 7 shows the percentage reduction in CD38+ CD138+ cell frequency in the bone marrow of patients after 4 hours of incubation in the presence of autologous CIML NK cells and daratumab or I-17. As shown in FIG. 7, I-17 effectively reduced the frequency of plasma cells (CD38+ CD138+) compared to control untreated bone marrow incubated with CIML NK cells.

The provided techniques do not significantly affect the immune cell population.

Furthermore, this example further demonstrates that the provided technology has low toxicity, especially when compared to therapies where the antibodies utilized are directed to the same target as ARM. As shown in FIG. 8 (frequency of CD56+ CD138-CIML NK cells when co-incubated with patient bone marrow and either daratumab or I-17 for 4 hours), NK cell number did not change in the presence of I-17, whereas darunavir showed a dose-dependent increase in NK cell suicide.

Example 8. the provided techniques can effectively reduce the number of target cells.

As described herein, the provided techniques can effectively reduce the number of target cells (e.g., cells expressing CD 38). Without intending to be limited by theory, in some embodiments, the reduction in the number of target cells may include or be mediated by ADCP, which in some cases is mediated by macrophages. Techniques for assessing provided compounds, compositions, and methods, as well as illustrative data demonstrating the activity of provided techniques (e.g., compounds, compositions, methods, etc.) are described below.

Materials and methods

Test system

Species/strain:	mouse/SCID
		Physiological state:	is normal
Age/body weight range at study start:	the animals were about 6 weeks old and about 25g in weight.
		Animal suppliers:	charles River Laboratory (Charles River Laboratory)
Number/sex of animals	32/female
		Marking:	ear number/transponder
Randomization:	animals were randomized prior to assignment to treatment groups.
		Adjusting:	mice represent a well characterized system for drug efficacy assessment.
And (3) replacing:	animals will not be replaced during the course of the study.

Design of experiments

On day 0, animals were weighed and randomized. Mice were assigned to different groups and treated as described below. CFSE labeled Daudi cells were prepared as follows:

CFSE staining of Daudi cells for IP injection:

the reagents used were: PBS (sterile)

Quenching buffer PBS + 10% FBS

RPMI (no additive), no P/S; FBS-free

Invitrogen-CellTrace CFSE cell proliferation kit for flow cytometry (Cat. No. C34570)

Sterile PBS and all other media were warmed to 37 degrees celsius prior to use for all the following steps listed below.

Sufficient cells were collected from the cell culture to contain 50% more cells than required for the analysis

Cells were washed 2 x with sterile PBS by centrifugation at 500g for 7 min.

The cells were resuspended in sterile PBS in a 50mL polypropylene tube to prepare a cell suspension such that the cell suspension occupied less than 1/4 of the total tube volume.

A 5mM stock solution of CFSE was prepared by adding 18 μ L DMSO to a lyophilized tube of CFSE.

The solution was diluted 10-fold from the stock solution in PBS to make a 100X (500. mu.M) solution

Add 10. mu.L or 100 XCFSE solution per 1mL of cells

CFSE stock solution was added to the resuspended cells so that the final concentration of CFSE was 5 μ M.

The cell suspension was gently mixed by vortexing until the density stabilized dmso (cfse) was no longer visible.

The cap of the 50mL conical tube (containing CFSE-labeled cells) was released, it was stood in a test tube rack, and it was placed in CO at 37 deg.C₂The incubator was left for 10 minutes while vortexing every 2 minutes.

After incubation, the tube was topped up with quench buffer for quenching and allowed to stand for 2 minutes.

Cells were washed 2 x by centrifugation at 500g for 7 min and rewashed with sterile quench buffer.

Cells were washed 3 x with cold sterile RPMI (without additives) by centrifugation at 500g for 7 min.

For each washing step, the volume is at most 50mL

Final cell count was performed:

cells were diluted 1: 50 in counting vials

Resuspend to desired cell density with approximate volume of cold RPMI (no additive):

modulating cell density

Cells will be injected per mouse: 400 μ L per mouse; total 20X 10 per mouse⁶An

After 16 to 18 hours, via CO₂Mice were sacrificed by asphyxiation and their peritoneal cavity was rinsed with 5ml PBS containing 1% BSA. The samples were processed and analyzed using the IP lavage process described in 00765. The samples were evaluated for tumor cell counts.

Study schedule:

animal body weights were measured and recorded at day 0 randomization. Additional body weight was collected at the time of administration of the same compound.

And (4) collecting tissues. After 16 to 18 hours, via CO₂Mice were sacrificed by asphyxiation and their peritoneal cavity was rinsed with 5mL PBS containing 1% BSA. The samples were kept on ice until further processing.

Applicable IP lavage treatment protocol:

1. intraperitoneal lavage was collected using 5ml of IgG free PBS 1% BSA.

2. Lavage samples were briefly centrifuged at 400g for 5 minutes.

3. The maintenance marks the tube as originally received from the animal facility and keeps the sample on ice.

4. The volume of each sample was recorded on a spreadsheet.

5. The supernatant was poured into 5ml Eppendorf (Eppendorf) tubes and stored at-80.

6. The pellet was resuspended in 250 μ L of PBS 1% BSA without IgG and transferred to a blue top filter flow tube.

7. The top filter tube was centrifuged briefly at 400g for 5 minutes.

8. The supernatant was poured into a waste tube.

RBC present? The following steps are continued:

a. RBC lysis was performed by resuspending the pellet in 1ml of RBC lysis buffer for 5 minutes at room temperature, adding 1ml of PBS 1% BSA buffer to each tube, and centrifuging for 5 minutes at 400g briefly.

b. The pellet was resuspended in 250 μ L of IgG-free PBS 1% BSA by pipetting up and down, and the whole cell suspension was transferred to a 96-well plate labeled with the sample number.

c. Plates were centrifuged briefly at 400g for 3 minutes and the supernatant was flicked off, and plates were placed on ice.

Applicable preparation protocol for flow analysis on Attune:

1. cells were resuspended in 250 μ L PBS 1% BSA without IgG in tubes.

2. Samples from the above steps were divided into 2 identical 96-well V-bottom plates.

3. And (3) fixing procedures:

a. fixation was performed in 4% paraformaldehyde (stock 16%, diluted 1: 4 with PBS).

b. Plates were centrifuged briefly at 400g for 5 minutes and the supernatant was flicked off.

c. Resuspend with 125 μ l IgG free PBS 1% BSA.

d. Add 125. mu.l of 4% paraformaldehyde with a pipette and mix gently.

e. Incubate at room temperature for 10 minutes.

f. Plates were centrifuged briefly at 400g for 5 minutes and the supernatant was flicked off.

g. Resuspended in 250. mu.l PBS 1% BSA without IgG.

h. Stored at 4 degrees celsius.

4. Run fixed samples:

a. the plate is removed from the refrigerator.

c. The CST beads were run on Attune and the experiment set up while the plate was briefly centrifuged.

d. Resuspend with 250 μ l of IgG free PBS 1% BSA.

Some of the data is presented in fig. 9. As demonstrated herein, the provided techniques can effectively reduce the number of target cells, as demonstrated by the dose-dependent reduction of Daudi cells in an intraperitoneal lavage model, which can be mediated via or including macrophage-dependent ADCP of Daudi cells, without intending to be limited by theory.

Example 9 compositions comprising cells can be cryopreserved.

In addition, the present disclosure demonstrates that compositions including cells can be cryopreserved and later utilized to provide a desired activity. In the examples:

CIML NK cells were produced from the same day arriving white blood cell package (leukopack) and had greater than 95% viability prior to freezing.

PBMC, NK cell isolation and CIML production were as described (e.g., example 6; scientific transformed Medicine, Romee et al, 2016, 9, 21, 9, 8, 357ra 123; digital object identifier: 10.1126/scitranslim. aaf2341).

3. CIML NK cells were washed free of cytokines with RPMI 10% FBS and twice.

4. Viability was assessed by trypan blue or L/D identification dyes (e.g., L/D near IR) prior to freezing.

5. Cells were frozen in FBS 10% DMSO at 100X 10^6 cells per vial per ml, or in the same medium + 25. mu. M I-17:

briefly, a 25mM stock of I-17 was generated in DMSO.

This was further diluted 1: 100 in DMSO to make 250. mu.M.

Preparing a freezing culture medium:

does not contain I-17: 90% FBS + 10% DMSO-was used for control cells.

Contains I-17: 90% FBS + 10% in DMSO 250 u M I-17 solution-for and I-17 together with frozen cells.

6. Cells were placed in a mister frost isopropanol container and stored at 80 ℃.

7. Cells were maintained at-80 for 1 day and then switched to liquid nitrogen.

8. Cells were maintained in liquid nitrogen for 2 weeks before thawing.

9. The vial was placed at 37H₂Thaw in O bath for more than 5 minutes.

10. Added dropwise to 35mL of warm RPMI 10% FBS.

11. Centrifuge at 400g for 10 min.

12. Wash 1 x with RPMI 10% FBS.

13. Centrifuge at 400g for 10 min.

14. The viability is counted and assessed using a near IR viability dye or the like.

15. Proceeding to ADCC: the CFSE-labeled MOLP8 cells were resuspended in 10 k/50. mu.l RPMI 10% FCS.

16. Add to round bottom 96-well plates.

17. NK cells were resuspended at 100K/50. mu.L, 50K and 25K and added to the target cells.

18. To CIML cell conditions were added 3. mu.g/mL of daratumab or 2.5. mu.M of I-17+ 10. mu.g/mL of IvIG.

19. To the wells receiving CIML NK cells frozen in combination with I-17, only IvIG was added.

20. Incubate for 4 hours.

21. Staining was done with IR L/D, CD107a and CD 69.

As shown in fig. 10, a composition comprising cells can be cryopreserved and then thawed and used with provided compounds (provided compounds in the same cryopreserved composition and/or added separately) to provide activity. In some embodiments, the cells are stored with a provided compound (e.g., an ARM agent). In some embodiments, the cells are not stored with the ARM agent provided, which can be added separately.

While we have described a number of embodiments, it is apparent that our basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It is, therefore, to be understood that the scope of the invention should be defined by the appended claims rather than the specific embodiments illustrated.

Claims

1. A medicament, comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

the optional presence of a linker moiety or moieties,

wherein the target binding moiety specifically binds to CD 38.

2. The agent of claim 1, wherein the agent has the structure of formula I:

each of a and b is independently 1 to 200;

each ABT is independently an antibody binding moiety;

l is a linker moiety connecting ABT and TBT; and is

Each TBT is independently a target binding moiety.

3. The agent of claim 1, wherein the agent has the structure:

or a pharmaceutically acceptable salt thereof, wherein:

and b is independently from 1 to 200;

each ABT is independently an antibody binding moiety;

l is a bivalent linker moiety linking ABT to TBT;

each Xaa is independently a residue of an amino acid or amino acid analog;

y is 5 to 20;

L^TTo link two of amino acids or amino acid analoguesLinker moieties of each independent residue, and independently being a covalent bond, or selected from C₁-C₆Aliphatic radical or C having 1 to 5 hetero atoms₁-C₆A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each R^cIndependently is-L^a-R′；

t is 0 to 50;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Each R is independently-H, or an optionally substituted group selected from: c_1-30Aliphatic radical, C having 1 to 10 heteroatoms _1-30Heteroaliphatic radical, C_6-30Aryl radical, C_6-30Arylaliphatic radical, C having 1 to 10 heteroatoms_6-30Aryl heteroaliphatic, 5-to 30-membered heteroaryl having 1 to 10 heteroatoms and 3-to 30-membered heterocyclyl having 1 to 10 heteroatoms, or

Optionally and independently, two R groups together form a covalent bond, or:

4. A medicament, comprising:

(ii) an antibody-binding moiety,

a target binding moiety, and

the optional presence of a linker moiety or moieties,

wherein the target binding moiety has the following structure:

each Xaa is independently a residue of an amino acid or amino acid analog;

y is 5 to 20;

L^Ta linker moiety which is two separate residues of an amino acid or amino acid analogue and is independently a covalent bond, or is selected from C ₁-C₆Aliphatic radical or C having 1 to 5 hetero atoms₁-C₆A heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of said radical are optionally and independently replaced by-C (R')₂-、-Cy-、-O-、-S-、-S-S-、-N(R′)-、-C(O)-、-C(S)-、-C(NR′)-、-C(O)N(R′)-、-N(R′)C(O)N(R′)-、-N(R′)C(O)O-、-S(O)-、-S(O)₂-、-S(O)₂N (R') -, -C (O) S-or-C (O) O-substitution;

each R^cIndependently is-L^a-R′；

t is 0 to 50;

each R' is independently-R, -C (O) R, -CO₂R or-SO₂R；

Optionally and independently, two R groups together form a covalent bond, or:

5. The medicament of claim 4, wherein- (Xaa) y-comprises:

-Xaa^T1-Xaa^T2-(Xaa)y′-Xaa^T3-Xaa^T4-Xaa^T5-，

wherein:

y' is 0 to 8;

Xaa^T5For C whose side chain is substituted ₁-C₈Aliphatic amino acids or amino acid analogues.

6. The medicament of claim 5, wherein Xaa^T1Is the residue of Ahp, Y, W, S, K or K (MePEG4 c).

7. The medicament of claim 6, wherein Xaa^T2Is the residue of Y, W, Ahp, Bph, L or A.

8. The medicament of claim 7, wherein Xaa^T3Is a residue of L, Ahp, V, T, Hse or MetO 2.

9. The medicament of claim 8, wherein Xaa^T4Residues of Bph, V or Ahp.

10. The medicament of claim 9, wherein Xaa^T5Residues of Ahp, Bph, Ado, Ano, PhNle or PhNva.

11. The medicament of claim 10, wherein- (Xaa) y-is or comprises:

wherein:

(Xaa)_a3is or comprises Xaa^T1；

(Xaa)_a4Is or comprises Xaa^T2；

(Xaa)_a9Is or comprises Xaa^T3；

(Xaa)_a10Is or comprises Xaa^T4(ii) a And is

(Xaa)_a11Is or comprises Xaa^T5。

12. The medicament of claim 11, wherein (Xaa)_a1Is or includes A, K or K (MePEG4 c).

13. The medicament of claim 12, wherein (Xaa)_a2Is or includes R, S, D, Y, A, W, K, 4Py2NH2, Cit, F3G, hCit, K (MePEG4c), RNdMe, RNMe or RNNdMe.

14. The medicament of claim 13, wherein (Xaa)_a5Is or includes H, Y, S, L, A, W or W6N.

15. The medicament of claim 14, wherein (Xaa)_a6Is or includes D, G, R, Y, H, W, A or Y.

16. The method of claim 15Medicament, wherein (Xaa)_a7Is or includes G, D, E, Q, N, R, MetO2, S, Har or A.

17. The medicament of claim 16, wherein (Xaa)_a8Is or includes V, A, D, G, W, S or T.

18. The medicament of claim 17, wherein (Xaa)_a12Is or includes D, A, S, G or Ahp.

19. The medicament of claim 18, wherein (Xaa)_a13Is or includes C.

20. The medicament of claim 4, wherein- (Xaa) y-comprises:

-Xaa^T6-(Xaa)y′-Xaa^T7-Xaa^T8-Xaa^T9-Xaa^T10-Xaa^T11-，

wherein:

y' is 0 to 8;

Xaa^T8is a residue of proline or an amino acid analogue thereof;

Xaa^T10for C whose side chain is substituted ₁-C₈A residue of an aliphatic group amino acid or an amino acid analog or a residue of an amino acid in which an amino group thereof is substituted; and is

Xaa^T11Including an optionally substituted aromatic group for its side chain or being optionally substituted C₁-C₈Aliphatic amino acidsOr a residue of an amino acid analog.

21. The medicament of claim 20, wherein Xaa^T6Is a residue of MeF, L or S.

22. The medicament of claim 21, wherein Xaa^T7Is a residue of L or MeF.

23. The medicament of claim 22, wherein Xaa^T8Is the residue of P.

24. The medicament of claim 23, wherein Xaa^T9Is a residue of Bph, D or S.

25. The medicament of claim 24, wherein Xaa^T10Is a residue of V or L.

26. The medicament of claim 25, wherein Xaa^T11Is a residue of W or R.

27. The medicament of claim 26, wherein- (Xaa) y-is or comprises:

wherein:

each of al, a2, a3, a4, a5, a6, a7, a8, a9, a10, a11, and a12 is independently 0 to 5;

(Xaa)_a4is or comprises Xaa^T6；

(Xaa)_a6Is or comprises Xaa^T7；

(Xaa)_a7Is or comprises Xaa^T8；

(Xaa)_a8Is or comprises Xaa^T9；

(Xaa)_a9Is or a bagInclude Xaa^T10(ii) a And is

(Xaa)_a10Is or comprises Xaa^T11。

28. The medicament of claim 27, wherein (Xaa)_a1Is or includes A.

29. The medicament of claim 28, wherein (Xaa)_a2Is or includes L, A or P.

30. The medicament of claim 29, wherein (Xaa)_a3Is or includes H, R or A.

31. The medicament of claim 30, wherein (Xaa)_a5Is or includes V, A or MeG.

32. The medicament of claim 31, wherein (Xaa)_a11Is or includes V, A, D or MeG.

33. The medicament of claim 32, wherein (Xaa)_a12Is or includes C.

34. The agent of claim 4, wherein the target binding moiety or

Is or comprises a sequence selected from SEQ ID NO: 1-34.

35. The medicament of any one of claims 4 to 34, wherein two Xaa are linked together.

36. The medicament of claim 35, wherein two Xaa are via a c- (o) -CH having₂-the linkers of the structure are linked together.

37. The agent of claim 36, wherein-c (o) -amino bonded to Xaa.

38. The agent of claim 37, wherein-CH₂-S-bonded to the side chain of Xaa.

39. The agent of claim 4, wherein the target binding moiety or

Is or comprise

Or a salt form thereof.

40. The agent of any one of claims 4-34, wherein the antibody binding portion can bind to two or more antibodies having different Fab regions.

41. The agent of any one of claims 4-34, wherein the antibody-binding portion has the structure DCAWHLGELVWCT or a salt form thereof, wherein two C residues are linked by-S-.

42. The agent of any one of claims 4-34, wherein the antibody binding moiety is or comprises optionally substituted

43. The agent of any one of claims 4 to 34, wherein the antibody binding moiety is or comprises

44. The agent of any one of the preceding claims, comprising a linker.

45. The agent of any one of the preceding claims, wherein the linker is or comprises- (CH)₂CH₂O) n-where n is 1 to 20.

46. The agent of any one of the preceding claims, wherein the linker comprises one or more amino acid residues.

47. The agent of any one of the preceding claims, wherein the linker comprises

48. A medicament, wherein the medicament is I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46 or I-47 or a pharmaceutically acceptable salt thereof.

49. The agent of any one of the preceding claims, wherein the agent binds to CD38 with a Kd of no more than 200, 100, 50, 40, 30, 20, 10, or 5nM as measured by SPR.

50. A composition comprising the agent of any one of the preceding claims and a population of cells.

51. The composition of claim 50, wherein the cell is or comprises an NK cell, an engineered NK cell, an ex vivo expanded NK cell, a memory-like NK cell, a cytokine-induced memory-like NK cell, an NKT cell, a monocyte and/or a macrophage.

52. A pharmaceutical composition comprising the agent or composition of any one of the preceding claims and a pharmaceutically acceptable carrier.

53. The composition of any one of claims 50-52, wherein the composition comprises an immunoglobulin.

54. The composition of claim 53, wherein the immunoglobulin is an intravenous immunoglobulin.

55. A method for treating a CD 38-associated condition, disorder or disease, comprising administering to a subject suffering from the CD 38-associated condition, disorder or disease an effective amount of the agent or composition of any one of the preceding claims.

56. The method of claim 55, comprising administering to the subject a population of cells.

57. The method of claim 56, wherein the subject is subjected to both the agent or composition and the population of cells.

58. The method of any one of claims 56-57, wherein the cell is or comprises an NK cell, an engineered NK cell, an ex vivo expanded NK cell, a memory-like NK cell, a cytokine-induced memory-like NK cell, an NKT cell, a monocyte and/or a macrophage.

59. The method of any one of claims 56-58, wherein the cell is administered concurrently with the agent or composition.

60. The method of any one of claims 56-59, wherein the cell and the agent or composition are administered simultaneously in the form of a composition comprising the cell and the agent or composition.

61. The method of any one of claims 56-58, wherein the cells are administered before or after administration of the agent or composition.

62. The method of any one of claims 55-61, wherein the method comprises administering intravenous immunoglobulin.

63. The method of claim 62, wherein the immunoglobulin is administered simultaneously with, before, or after the agent or composition.

64. The method of any one of the preceding claims, wherein one or more doses of the cells of any one of the preceding claims and/or one or more doses of the cells of any one of the preceding claims and the agent of any one of the preceding claims are administered after administration of the agent.

65. A method, comprising:

a) providing a first compound comprising a target binding moiety as described in any one of the preceding claims and a first reactive group;

b) providing a second compound comprising an antibody binding moiety as described in any one of the preceding claims and a second reactive group; and

66. The method of claim 65, wherein the first compound is a compound of formula V or a salt thereof.

67. The method of claim 65 or 66, wherein the second compound is a compound of formula IV, IV-a, IV-b, IV-c, or IV-d, or a salt thereof.

68. A method for manufacturing the agent or composition of any one of the preceding claims, comprising reacting a first compound comprising an antibody binding moiety and an alkyne with a second compound comprising a target binding moiety and an azide, or reacting a first compound comprising an antibody binding moiety and an azide with a second compound comprising a target binding moiety and an alkyne.

69. A method for recruiting an antibody to a target comprising or expressing CD38, comprising contacting the target with an agent or composition of any one of the preceding claims.

70. A method for recruiting immune activity to a target comprising or expressing CD38, comprising contacting the target with an agent of any one of the preceding claims.

71. The method of any one of claims 69-70, wherein the target is a tumor cell.

72. A compound, agent, composition or method as described in any one of embodiments 1-367.